Pyrazole and imidazole derivatives as dual modulators of orexin and kappa opioid receptors, compositions, and therapies for the treatment of neurological and psychiatric disorders

Abstract

The present disclosure is directed to substituted pyrazole and imidazole derivatives of compounds that are orexin receptor and kappa opioid receptor antagonists and / or modulators and are useful in the treatment or prevention of neurological, psychiatric, cardiovascular, and cancerous diseases, as well as diseases in which orexin receptors and kappa opioid receptors are implicated or associated. The present disclosure is also directed to pharmaceutical compositions comprising these compounds, and to the use of these compounds and compositions in the prevention or treatment of such diseases in which orexin receptors and kappa opioid receptors are implicated.

Description

[Technical Field]

[0001] Related Applications This application claims priority to U.S. Patent Application No. 63 / 403,019, filed September 1, 2022, the entire contents of which are incorporated herein by reference.

[0002] The present disclosure relates to compounds, compositions, and methods of treatment that utilize dual-acting antagonists and / or modulators of orexin receptors and kappa opioid receptors as therapeutic agents for treating or ameliorating human and animal diseases, particularly any pathological disorder in which both orexin receptors and kappa opioid receptors are pharmacologically implicated or linked. These important therapeutic applications include, but are not limited to, the treatment of central nervous system (CNS) disorders, neurological disorders, and cardiovascular diseases, including various cancers, that involve or are modulated by orexin receptors and / or kappa opioid receptors; such disorders and diseases include, but are not limited to, substance addiction and dependence, cognitive impairment, Alzheimer's disease (AD), post-traumatic stress disorder (PTSD), schizophrenia, panic, anxiety, autism, pain, and depression, which are responsive to orexin receptor and / or kappa opioid receptor antagonists.

[0003] Explanation of research funding from the U.S. federal government This disclosure was made in part with government support under Federal Research Grant Number: UF1DA054817 awarded by the National Institute on Drug Abuse, part of the National Institutes of Health. The federal government has certain rights in this disclosure. [Background technology]

[0004] Orexins (also known as hypocretins) are composed of two excitatory hypothalamic neuropeptides, orexin A (OX-A; a 33-amino acid peptide) and orexin B (OX-B; a 28-amino acid peptide), which were discovered by two research groups searching for novel signaling molecules: (1) Sakurai and coworkers (who named them orexin-A and -B) (Sakurai, T. et al., Cell 1998, 92, 573); and (2) de Lecea and coworkers, who named them hypocretin 1 and hypocretin 2, respectively (de Lecea, L. et al., Proc. Natl. Acad. Sci. USA 1998, 95, 322); They were discovered simultaneously in 1998 by These neuropeptides are endogenous ligands for two G protein-coupled receptors (GPCRs), OX1R and OX2R (also known as Hcrt1 and Hcrt2, respectively), and are derived by proteolysis from the same precursor peptide, the prepro-orexin polypeptide (Sakurai T. et al., The Journal of Biological Chemistry, 1999;274, 17771-17776). Although these endogenous ligands are structurally related, they have different binding affinities for the two GPCRs. Orexin A binds to OX1R with approximately 100-fold higher affinity than orexin B, whereas both orexin A and orexin B bind to OX2R with similar affinity (Kodadek, T.; Cai, D., Mol. BioSyst., 2010,6,1366-1375). Shortly after the discovery of orexin, modulation of orexin signaling was first explored as a potential novel therapeutic approach for patients with narcolepsy or insomnia; the role of orexin in regulating sleep and wakefulness was well studied and understood, and the discovery of small molecule modulators of orexin signaling facilitated the development of this class of compounds. Patients with narcolepsy exhibit reduced activity of hypothalamic orexin neurons, which reduces the amount of circulating orexin in the cerebrospinal fluid. In contrast, activation of orexin neurons maintains wakefulness and alertness. The effects of orexin signaling on feeding and energy homeostasis have also been previously documented and shown to be coordinated with the sleep-wake cycle (Kodadek, T.; Cai, D. Mol. BioSyst., 2010, 6, 1366-1375).More recent studies have revealed roles for orexin and / or kappa opioid signaling in other key physiological pathways, such as neuroendocrine function (Inutsuka, A.; Yamanaka, A. Front. Endocrinol. 2013, 4:18. doi:10.3389 / fendo.2013.00018), glucose metabolism (Tsuneki, H. et al., Endocrinology, 2016, 157, 4146-4157), stress-adaptive responses (Xiao, F. et al., Neuropharmacology, 2013, 67, 16-24), and addiction / reward-seeking (Aston-Jones, G. et al., Brain Res., 2010, 1314, 74-90). Small molecule orexin antagonists have been broadly classified into three classes based on their overall receptor selectivity profiles: That is, (1) DORA (dual-acting or non-selective OX1R / OX2R antagonists), (2) SORA-1 (selective OX1R antagonist), and (3) SORA-2 (selective OX2R antagonist). Both OX2R knockout mice and OX1R / OX2R double knockout mice exhibit a somnologenic phenotype, but the effect is significantly weaker in OX1R knockout mice (Wang C et al., Neurosci., 2018, 11, 220. doi:10.3389 / fnmol2018.00220). Furthermore, while both DORA and SORA-2 compounds disrupt wakefulness, SORA-1 compounds do not; this suggests that the somnologenic effect is mediated by OX2R or a combination of OX1R and OX2R, but not by OX1R alone. Therefore, the discovery and development of differentiated orexin antagonists is crucial for advancing the field, and even more importantly, for the development of therapeutics for dysregulated biological processes involving orexin receptors, particularly for sleep-related conditions (e.g., substance addiction, anxiety, panic, and PTSD).

[0005] Kappa opioid receptor (κOR) Opioid research has focused on the development of new drugs for CNS or neuropsychiatric disorders through modulation of the endogenous opioid system (mu, kappa, and delta opioid receptors (MOR, κOR, DOR) and their endogenous ligand peptides, e.g., β-endorphins, dynorphins, and enkephalins, respectively). More specifically (i.e., preferably), κOR antagonists have shown potential utility in the treatment of stress-related mood disorders, including depression, anxiety, and substance abuse. Stressful stimuli, particularly those occurring during withdrawal, induce activation of κOR by its endogenous ligand, dynorphin. This stress-induced depressive disorder contributes to relapse to drug-seeking behavior, which has been shown to be attenuated by κOR antagonists. In contrast, stimulation of κOR by either its endogenous ligand, dynorphin, or synthetic agonists, such as opioids, is known to exert antinociceptive and analgesic effects.

[0006] Co-modulation of different molecular targets or receptors that are both involved in a common disease pathway or disorder, using a single molecular entity, may provide better overall efficacy compared to administering either a cocktail of drugs or a single pill containing a multi-component drug. Potential advantages of a dual target modulation approach compared to drug combinations or cocktails include, but are not limited to: That is, Improved dosing regimens and compliance, reduced drug-drug interactions, simplified and predictable PK / PD relationships and one-dimensional DMPK and safety profiles, potentially synergistic efficacy, reduced likelihood of resistance, and fewer regulatory barriers. In treating conditions with multifactorial and complex etiologies, such as CNS and / or neurological disorders, cancer, metabolic syndrome, and cardiovascular disease, and more specifically (i.e., preferred) abuse disorders, the network pharmacology approach described above may provide superior efficacy compared to single-targeted agents. Thus, coordinated yet balanced co-regulation of orexin receptors and kappa opioid receptors (OXR and κOR) (e.g., OXR antagonists and κOR partial antagonists or inverse agonists or agonists) may provide novel molecular entities for unique and innovative, highly effective therapeutic agents for numerous dysregulated biological processes involving orexin receptors and / or kappa opioid receptors. The compounds, compositions, and methods provide solutions to these problems in the art. Summary of the Invention

[0007] In different embodiments, the present disclosure provides compounds of Formula I or II: [ka] The aforementioned therapeutic needs are addressed by providing compounds of the formula I or II, wherein the variants are defined herein, including any pharmaceutically acceptable salts, solvates, adducts, polymorphs, and isomers thereof. Compounds of formula I or II can be used to treat the conditions described herein, such as by modulating orexin receptors and / or kappa opioid receptors, respectively. In some embodiments, the compounds provide balanced co-modulation of orexin receptors and kappa opioid receptors (OXR and κOR) (e.g., antagonists of OXR and partial antagonists or inverse agonists or agonists of κOR).

[0008] The present disclosure also provides a composition comprising the compound or a pharmaceutically acceptable salt thereof. In another aspect, the present disclosure provides a method for treating a CNS disorder, particularly substance addiction and dependence, post-traumatic stress disorder (PTSD), schizophrenia, panic, anxiety, pain, depression, cognitive impairment, and Alzheimer's disease (AD), in a subject in need of treatment or at risk of such a disorder, comprising administering to the subject a therapeutically effective amount of an orexin receptor and / or kappa opioid receptor antagonist and / or modulator, or a pharmaceutically acceptable salt thereof. In certain embodiments of the present disclosure, the antagonist and / or modulator, or a pharmaceutically acceptable salt thereof, can be administered periodically, for example, every 3 hours, every 6 to 24 hours, or weekly, as deemed clinically beneficial. DETAILED DESCRIPTION OF THE INVENTION

[0009] The present disclosure relates to derivatives of the fused 6- and 5-membered ring systems of formula (I) and / or (II), as set forth in the complete disclosure where the fused 6- and 5-membered rings are structurally describable, as well as pharmaceutically acceptable salts thereof, preparations thereof, pharmaceutical compositions comprising one or more compounds of formula (I) and / or (II), and their use as medicines and therapeutic agents, in particular as antagonists and / or modulators of orexin receptors and / or kappa opioid receptors. These novel chemical entities, such as those represented by formulas (I) and / or (II), are non-peptide modulators of human orexin receptors and / or kappa opioid receptors and are potentially useful in the treatment of disorders associated with orexinergic and kappa opioid receptor dysfunction, including, but not limited to, the treatment of disorders such as substance abuse, anxiety, panic, cognitive dysfunction, mood, or appetite, sleep, Alzheimer's disease (AD), metabolic syndrome, and hypertension; and in particular, these compounds may be of therapeutic value in the treatment of anxiety disorders, pain, abuse disorders, and sleep disorders.

[0010] A first aspect of the present disclosure is a compound represented by the following formula (I) or (II): [ka] The present invention relates to a compound of the formula R1 includes E, which is a carbon (C) but not a nitrogen (N), and E is connected to J or D by a double bond; and R1 is selected from the group consisting of H, alkyl, alkoxy, cycloalkyl, phenyl, aromatic or aryl, heteroaryl (5-6 membered ring), substituted aromatic or aryl, substituted heteroaryl (5-6 membered ring); Alternatively, when R1 is heteroaryl, R1 is preferably a 5- or 6-membered heteroaryl selected from the group consisting of pyrazolyl, triazolyl, oxazolyl, thiazolyl, thiophenyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl; wherein said aromatic, aryl or heteroaryl is unsubstituted, mono- or di-substituted; wherein the substituents are independently: (C 1~4 ) alkyl, (C 1~4 ) alkoxy, halogen, (C 1~3 ) fluoroalkyl, (C 1~3 ) fluoroalkoxy and (C 3~7 ) cycloalkyl; R2, R3, and R4 are independently H, halogen (F, Cl, Br, etc.), alkyl, substituted alkyl, (C 1~4 ) alkyl, (C 1~4 ) alkoxy, (C 1~3 ) fluoroalkyl, (C 1~3 ) fluoroalkoxy and (C 3~7 ) cycloalkyl; wherein each of R2, R3, and R4 is independently and optionally substituted at each substitutable position with up to three independently selected substituents of one, two, or all of R2, R3, and R4; R5 is H, F, CH3, alkyl, substituted alkyl, (C 1~3 ) fluoroalkyl, cycloalkyl, and R5 is substituted at the carbon bearing Y, Z1, and Z2, where R5' is defined herein; R5' is an aromatic or aryl, heteroaryl (5-6 membered ring), substituted aromatic or aryl, substituted heteroaryl or fused two heteroaryl ring systems (5-6 membered ring); wherein said aromatic, aryl or heteroaryl is unsubstituted, mono- or di- or tri-substituted; wherein the substituents are independently: (C 1~4 ) alkyl, (C 1~4 ) alkoxy, halogen, (C 1~3 ) fluoroalkyl, (C 1~3 ) fluoroalkoxy, (C 3~7 ) cycloalkyl, (C 3~7 ) heterocycloalkyl; R6 is H, F, CH3, alkyl, substituted alkyl, (C 1~3 ) fluoroalkyl, cycloalkyl, and R6 is (C 1~3 ) R as alkyl to form a cyclic structure of alkyl bridge 10 or R 11 connected to either of the following; R7 is H, F, CH3, alkyl, substituted alkyl, (C 1~3 ) fluoroalkyl, cycloalkyl, and R7 is substituted at the carbon bearing Y, Z1, and Z2, where R5' is defined herein; R8 is H, F, CH3, alkyl, substituted alkyl, (C 1~3 ) fluoroalkyl, cycloalkyl, and R8 is (C 1~3) R as alkyl to form a cyclic structure of alkyl bridge 10 , R 11 or R 12 connected to one of the following: R9 is H, F, CH3, alkyl, substituted alkyl, (C 1~3 ) fluoroalkyl, cycloalkyl, and R9 is (C 1~3 ) R6 or R as alkyl forming the cyclic structure of the alkyl bridge 12 connected to either of the following; R 10 is H, F, CH3, alkyl, substituted alkyl, (C 1~3 ) fluoroalkyl, cycloalkyl, or R 10 (C 1~3 ) R6 or R as alkyl forming the cyclic structure of the alkyl bridge 11 is connected to; R 11 is H, F, CH3, alkyl, substituted alkyl, (C 1~3 ) fluoroalkyl, cycloalkyl, or R 11 (C 1~3 ) linked to R6 as an alkyl forming a cyclic structure of the alkyl bridge; R 12 is H, F, CH3, alkyl, substituted alkyl, (C 1~3 ) fluoroalkyl, cycloalkyl, or R 12 (C 1~3 ) linked to R9 as an alkyl forming a cyclic structure of the alkyl bridge; X may be empty (e.g., to provide a five-membered pyrrolidine ring) or may be CH2, O, CR a R b (where R a and R b is alkyl, cycloalkyl, or fluoroalkyl; Here, it is preferred that the carbon atom at position 2 of the piperidine or pyrrolidine has an absolute (S) configuration; In contrast, the carbon atom at position 2 of the morpholine ring is preferably in the absolute (R) configuration (when X is O, i.e., oxygen); Y is either empty (R5' is directly connected to the carbon bearing the Z1 and Z2 groups) or O, NH, CH2OR5', CH2, NR a (where R a is alkyl, cycloalkyl, or heteroalkyl), Alternatively, Y may be selected as a preferred linker and be a 5- or 6-membered heteroaryl selected from the group consisting of pyrrolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, oxadiazolyl; and Z1 and Z2 are H, F, (C 1~4 ) alkyl, (C 1~3 ) fluoroalkyl, (C 1~3 ) fluoroalkoxy, (C 2~7 ) cycloalkyl or independently selected from one of these groups; Also here: The fused or unfused ring system ABJDE is a 5-membered heteroaryl fused or unfused with a further ring system, such as imidazole (where A, J are nitrogen and B, E, D are carbon), pyrazole (where A, B are nitrogen and D, E, J are carbon); The fused ring system BJMGKL is an arrangement of the variables outlined above to provide the group consisting of 6-membered aromatic, 6-membered aryl, 6-membered substituted aromatic, 6-membered substituted aryl, 6-membered substituted heteroaryl, 6-membered unsubstituted heteroaryl, 5- or 6-membered cycloalkyl, and 5- or 6-membered heterocycloalkyl; wherein the preferred groups are: A = nitrogen (e.g., imidazole or pyrazole ring systems); B = carbon or nitrogen J = carbon or nitrogen D = carbon E = carbon, where R1 is as defined above; M = carbon, CH, CHR2, CHR3, CR2R3, CR2, CR3, CR4, O, N; G = carbon, CH, CHR2, CHR3, CR2R3, CR2, CR3, CR4, O; K = carbon, CH, CHR2, CHR3, CR2R3, CR2, CR3, CR4, O; and L = carbon, CH, CHR2, CHR3, CR2R3, CR2, CR3, CR4, O, and N.

[0011] In a more specific (i.e., preferred) embodiment, the present disclosure provides compounds of formula Ia and II-a, wherein the ring system fused to the six-membered ring (represented by the ABJDE variables in formula (I) or (II)) is preferred as the imidazolo ring system represented by embodiment formula Ia or II-a; embodiments formula Ia and II-a herein are, respectively: [ka] where R1 is selected from the group consisting of H, alkyl, alkoxy, cycloalkyl, phenyl, aromatic or aryl, heteroaryl (5-6 membered ring), substituted aromatic or aryl, substituted heteroaryl (5-6 membered ring); Alternatively, when R1 is heteroaryl, R1 is preferably a 5- or 6-membered heteroaryl selected from the group consisting of pyrazolyl, triazolyl, oxazolyl, thiazolyl, thiophenyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl; wherein said aromatic, aryl or heteroaryl is unsubstituted, mono- or di-substituted; wherein the substituents are independently: (C 1~4 ) alkyl, (C 1~4 ) alkoxy, halogen, (C 1~3 ) fluoroalkyl, (C 1~3 ) fluoroalkoxy and (C 3~7 ) cycloalkyl; R2, R3, and R4 are independently H, halogen (F, Cl, Br, etc.), alkyl, substituted alkyl, (C 1~4 ) alkyl, (C 1~4 ) alkoxy, (C 1~3 ) fluoroalkyl, (C 1~3 ) fluoroalkoxy and (C 3~7 ) cycloalkyl; wherein each of R2, R3, and R4 is independently and optionally substituted at each substitutable position with up to three independently selected substituents of one, two, or all of R2, R3, and R4; R5 is H, F, CH3, alkyl, substituted alkyl, (C 1~3 ) fluoroalkyl, cycloalkyl, and R5 is substituted at the carbon bearing Y, Z1, and Z2, where R5' is defined herein; R5' is an aromatic or aryl, heteroaryl (5-6 membered ring), substituted aromatic or aryl, substituted heteroaryl or fused two heteroaryl ring systems (5-6 membered ring); wherein said aromatic, aryl or heteroaryl is unsubstituted, mono- or di- or tri-substituted; wherein the substituents are independently: (C 1~4 ) alkyl, (C 1~4 ) alkoxy, halogen, (C 1~3 ) fluoroalkyl, (C 1~3 ) fluoroalkoxy, (C 3~7 ) cycloalkyl, (C 3~7 ) heterocycloalkyl; R6 is H, F, CH3, alkyl, substituted alkyl, (C 1~3 ) fluoroalkyl, cycloalkyl, and R6 is (C 1~3 ) R as alkyl to form a cyclic structure of alkyl bridge 10 or R 11 connected to either of the following; R7 is H, F, CH3, alkyl, substituted alkyl, (C1~3 ) fluoroalkyl, cycloalkyl, and R7 is substituted at the carbon bearing Y, Z1, and Z2, where R5' is defined herein; R8 is H, F, CH3, alkyl, substituted alkyl, (C 1~3 ) fluoroalkyl, cycloalkyl, and R8 is (C 1~3 ) R as alkyl to form a cyclic structure of alkyl bridge 10 , R 11 or R 12 connected to either of the following; R9 is H, F, CH3, alkyl, substituted alkyl, (C 1~3 ) fluoroalkyl, cycloalkyl, and R9 is (C 1~3 ) R6 or R as alkyl forming the cyclic structure of the alkyl bridge 12 connected to either of the following; R 10 is H, F, CH3, alkyl, substituted alkyl, (C 1~3 ) fluoroalkyl, cycloalkyl, or R 10 (C 1~3 ) R6 or R as alkyl forming the cyclic structure of the alkyl bridge 11 is connected to; R 11 is H, F, CH3, alkyl, substituted alkyl, (C 1~3 ) fluoroalkyl, cycloalkyl, or R 11 (C 1~3 ) linked to R6 as an alkyl forming a cyclic structure of the alkyl bridge; R 12 is H, F, CH3, alkyl, substituted alkyl, (C 1~3 ) fluoroalkyl, cycloalkyl, or R 12 (C 1~3 ) linked to R9 as an alkyl forming a cyclic structure of the alkyl bridge; X may be empty (e.g., to provide a five-membered pyrrolidine ring) or may be CH2, O, CR a R b (where Ra and R b is alkyl, cycloalkyl, or fluoroalkyl; Here, it is preferred that the carbon atom at position 2 of the piperidine or pyrrolidine has an absolute (S) configuration; In contrast, the carbon atom at position 2 of the morpholine ring is preferably in the absolute (R) configuration (when X is O, i.e., oxygen); Y is either empty (R5' is directly connected to the carbon bearing the Z1 and Z2 groups) or O, NH, CH2OR5', CH2, NR a (where R a is alkyl, cycloalkyl, or heteroalkyl), Alternatively, Y may be selected as a preferred linker and be a 5- or 6-membered heteroaryl selected from the group consisting of pyrrolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, oxadiazolyl; and Z1 and Z2 are H, F, (C 1~4 ) alkyl, (C 1~3 ) fluoroalkyl, (C 1~3 ) fluoroalkoxy, (C 2~7 ) cycloalkyl or independently selected from one of these groups; Also here: The fused ring system BJMGKL is an arrangement of the variables outlined above to provide the group consisting of 6-membered aromatic, 6-membered aryl, 6-membered substituted aromatic, 6-membered substituted aryl, 6-membered substituted heteroaryl, 6-membered unsubstituted heteroaryl, 5- or 6-membered cycloalkyl, and 5- or 6-membered heterocycloalkyl; wherein the preferred groups are: M = carbon, CH, CHR2, CHR3, CR2R3, CR2, CR3, CR4, O, N; G = carbon, CH, CHR2, CHR3, CR2R3, CR2, CR3, CR4, O; K = carbon, CH, CHR2, CHR3, CR2R3, CR2, CR3, CR4, O; and L = carbon, CH, CHR2, CHR3, CR2R3, CR2, CR3, CR4, O, and N.

[0012] In a more specific (i.e., preferred) embodiment, the present disclosure provides compounds of formula Ib and II-b, wherein the ring system fused to the six-membered ring (represented by the ABJDE variables in formula (I) or (II)) is preferred as is the pyrazolo ring system represented by embodiment formula Ib or II-b; In embodiments herein, Formulas Ib and II-b are respectively: [ka] where R1 is selected from the group consisting of H, alkyl, alkoxy, cycloalkyl, phenyl, aromatic or aryl, heteroaryl (5-6 membered ring), substituted aromatic or aryl, substituted heteroaryl (5-6 membered ring); Alternatively, when R1 is heteroaryl, R1 is preferably a 5- or 6-membered heteroaryl selected from the group consisting of pyrazolyl, triazolyl, oxazolyl, thiazolyl, thiophenyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl; wherein said aromatic, aryl or heteroaryl is unsubstituted, mono- or di-substituted; wherein the substituents are independently: (C 1~4 ) alkyl, (C 1~4 ) alkoxy, halogen, (C 1~3 ) fluoroalkyl, (C 1~3 ) fluoroalkoxy and (C 3~7 ) cycloalkyl; R2, R3, and R4 are independently H, halogen (F, Cl, Br, etc.), alkyl, substituted alkyl, (C 1~4 ) alkyl, (C 1~4 ) alkoxy, (C 1~3 ) fluoroalkyl, (C 1~3) fluoroalkoxy and (C 3~7 ) cycloalkyl; wherein each of R2, R3, and R4 is independently and optionally substituted at each substitutable position with up to three independently selected substituents of one, two, or all of R2, R3, and R4; R5 is H, F, CH3, alkyl, substituted alkyl, (C 1~3 ) fluoroalkyl, cycloalkyl, and R5 is substituted at the carbon bearing Y, Z1, and Z2, where R5' is defined herein; R5' is an aromatic or aryl, heteroaryl (5-6 membered ring), substituted aromatic or aryl, substituted heteroaryl or fused two heteroaryl ring systems (5-6 membered ring); wherein said aromatic, aryl or heteroaryl is unsubstituted, mono- or di- or tri-substituted; wherein the substituents are independently: (C 1~4 ) alkyl, (C 1~4 ) alkoxy, halogen, (C 1~3 ) fluoroalkyl, (C 1~3 ) fluoroalkoxy, (C 3~7 ) cycloalkyl, (C 3~7 ) heterocycloalkyl; R6 is H, F, CH3, alkyl, substituted alkyl, (C 1~3 ) fluoroalkyl, cycloalkyl, and R6 is (C 1~3 ) R as alkyl to form a cyclic structure of alkyl bridge 10 or R 11 connected to either of the following; R7 is H, F, CH3, alkyl, substituted alkyl, (C 1~3 ) fluoroalkyl, cycloalkyl, and R7 is substituted at the carbon bearing Y, Z1, and Z2, where R5' is defined herein; R8 is H, F, CH3, alkyl, substituted alkyl, (C 1~3) fluoroalkyl, cycloalkyl, and R8 is (C 1~3 ) R as alkyl to form a cyclic structure of alkyl bridge 10 , R 11 or R 12 connected to either of the following; R9 is H, F, CH3, alkyl, substituted alkyl, (C 1~3 ) fluoroalkyl, cycloalkyl, and R9 is (C 1~3 ) R6 or R as alkyl forming the cyclic structure of the alkyl bridge 12 connected to either of the following; R 10 is H, F, CH3, alkyl, substituted alkyl, (C 1~3 ) fluoroalkyl, cycloalkyl, or R 10 (C 1~3 ) R6 or R as alkyl forming the cyclic structure of the alkyl bridge 11 is connected to; R 11 is H, F, CH3, alkyl, substituted alkyl, (C 1~3 ) fluoroalkyl, cycloalkyl, or R 11 (C 1~3 ) linked to R6 as an alkyl forming a cyclic structure of the alkyl bridge; R 12 is H, F, CH3, alkyl, substituted alkyl, (C 1~3 ) fluoroalkyl, cycloalkyl, or R 12 (C 1~3 ) linked to R9 as an alkyl forming a cyclic structure of the alkyl bridge; X may be empty (e.g., to provide a five-membered pyrrolidine ring) or may be CH2, O, CR a R b (where R a and R b is alkyl, cycloalkyl, or fluoroalkyl; Here, it is preferred that the carbon atom at position 2 of the piperidine or pyrrolidine has an absolute (S) configuration; In contrast, the carbon atom at position 2 of the morpholine ring is preferably in the absolute (R) configuration (when X is O, i.e., oxygen); Y is either empty (R5' is directly connected to the carbon bearing the Z1 and Z2 groups) or O, NH, CH2OR5', CH2, NR a (where R a is alkyl, cycloalkyl, or heteroalkyl; Alternatively, Y may be selected as a preferred linker and be a 5- or 6-membered heteroaryl selected from the group consisting of pyrrolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, oxadiazolyl; and Z1 and Z2 are H, F, (C 1~4 ) alkyl, (C 1~3 ) fluoroalkyl, (C 1~3 ) fluoroalkoxy, (C 2~7 ) cycloalkyl or independently selected from one of these groups; Also here: The fused ring system BJMGKL is an arrangement of the variables outlined above to provide the group consisting of 6-membered aromatic, 6-membered aryl, 6-membered substituted aromatic, 6-membered substituted aryl, 6-membered substituted heteroaryl, 6-membered unsubstituted heteroaryl, 5- or 6-membered cycloalkyl, and 5- or 6-membered heterocycloalkyl; wherein the preferred groups are: M = carbon, CH, CHR2, CHR3, CR2R3, CR2, CR3, CR4, O, N; G = carbon, CH, CHR2, CHR3, CR2R3, CR2, CR3, CR4, O; K = carbon, CH, CHR2, CHR3, CR2R3, CR2, CR3, CR4, O; and L = carbon, CH, CHR2, CHR3, CR2R3, CR2, CR3, CR4, O, and N.

[0013] A further embodiment of the present disclosure relates to preferred compounds wherein the imidazole-fused 6-membered ring is preferably according to embodiment formula I-a1 or II-a1 herein, where embodiment formula I-a1 and II-a1 are respectively: [ka] where R1 is selected from the group consisting of H, alkyl, alkoxy, cycloalkyl, phenyl, aromatic or aryl, heteroaryl (5-6 membered ring), substituted aromatic or aryl, substituted heteroaryl (5-6 membered ring); Alternatively, when R1 is heteroaryl, R1 is preferably a 5- or 6-membered heteroaryl selected from the group consisting of pyrazolyl, triazolyl, oxazolyl, thiazolyl, thiophenyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl; wherein said aromatic, aryl or heteroaryl is unsubstituted, mono- or di-substituted; wherein the substituents are independently: (C 1~4 ) alkyl, (C 1~4 ) alkoxy, halogen, (C 1~3 ) fluoroalkyl, (C 1~3 ) fluoroalkoxy and (C 3~7 ) cycloalkyl; R2, R3, and R4 are independently H, halogen (F, Cl, Br, etc.), alkyl, substituted alkyl, (C 1~4 ) alkyl, (C 1~4 ) alkoxy, (C 1~3 ) fluoroalkyl, (C 1~3 ) fluoroalkoxy and (C 3~7 ) cycloalkyl; wherein each of R2, R3, and R4 is independently and optionally substituted at each substitutable position with up to three independently selected substituents of one, two, or all of R2, R3, and R4; R5 is H, F, CH3, alkyl, substituted alkyl, (C 1~3 ) fluoroalkyl, cycloalkyl, and R5 is substituted at the carbon bearing Y, Z1, and Z2, where R5' is defined herein; R5' is an aromatic or aryl, heteroaryl (5-6 membered ring), substituted aromatic or aryl, substituted heteroaryl or fused two heteroaryl ring systems (5-6 membered ring); wherein said aromatic, aryl or heteroaryl is unsubstituted, mono- or di- or tri-substituted; wherein the substituents are independently: (C 1~4 ) alkyl, (C 1~4 ) alkoxy, halogen, (C 1~3 ) fluoroalkyl, (C 1~3 ) fluoroalkoxy, (C 3~7 ) cycloalkyl, (C 3~7 ) heterocycloalkyl; R6 is H, F, CH3, alkyl, substituted alkyl, (C 1~3 ) fluoroalkyl, cycloalkyl, and R6 is (C 1~3 ) R as alkyl to form a cyclic structure of alkyl bridge 10 or R 11 connected to either of the following; R7 is H, F, CH3, alkyl, substituted alkyl, (C 1~3 ) fluoroalkyl, cycloalkyl, and R7 is substituted at the carbon bearing Y, Z1, and Z2, where R5' is defined herein; R8 is H, F, CH3, alkyl, substituted alkyl, (C 1~3 ) fluoroalkyl, cycloalkyl, and R8 is (C 1~3 ) R as alkyl to form a cyclic structure of alkyl bridge 10 , R 11 or R 12 connected to either of the following; R9 is H, F, CH3, alkyl, substituted alkyl, (C 1~3) fluoroalkyl, cycloalkyl, and R9 is (C 1~3 ) R6 or R as alkyl forming the cyclic structure of the alkyl bridge 12 connected to either of the following; R 10 is H, F, CH3, alkyl, substituted alkyl, (C 1~3 ) fluoroalkyl, cycloalkyl, or R 10 (C 1~3 ) R6 or R as alkyl forming the cyclic structure of the alkyl bridge 11 is connected to; R 11 is H, F, CH3, alkyl, substituted alkyl, (C 1~3 ) fluoroalkyl, cycloalkyl, or R 11 (C 1~3 ) linked to R6 as an alkyl forming a cyclic structure of the alkyl bridge; R 12 is H, F, CH3, alkyl, substituted alkyl, (C 1~3 ) fluoroalkyl, cycloalkyl, or R 12 (C 1~3 ) linked to R9 as an alkyl forming a cyclic structure of the alkyl bridge; X may be empty (e.g., to provide a five-membered pyrrolidine ring) or may be CH2, O, CR a R b (where R a and R b is alkyl, cycloalkyl, or fluoroalkyl; Here, it is preferred that the carbon atom at position 2 of the piperidine or pyrrolidine has an absolute (S) configuration; In contrast, the carbon atom at position 2 of the morpholine ring is preferably in the absolute (R) configuration (when X is O, i.e., oxygen); Y is either empty (R5' is directly connected to the carbon bearing the Z1 and Z2 groups) or O, NH, CH2OR5', CH2, NR a (where R a is alkyl, cycloalkyl, or heteroalkyl; Alternatively, Y may be selected as a preferred linker and be a 5- or 6-membered heteroaryl selected from the group consisting of pyrrolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, oxadiazolyl; and Z1 and Z2 are H, F, (C 1~4 ) alkyl, (C 1~3 ) fluoroalkyl, (C 1~3 ) fluoroalkoxy, (C 2~7 ) cycloalkyl or independently selected from one of these groups; wherein the preferred groups are: L = carbon, CH, CHR2, CHR3, CR2R3, CR2, CR3, CR4, and N.

[0014] A further embodiment of the present disclosure relates to compounds wherein the imidazole-fused 6-membered ring is preferably according to embodiment formula I-a2 or II-a2 herein, where embodiment formulas I-a2 and II-a2 are respectively: [ka] where R1 is selected from the group consisting of H, alkyl, alkoxy, cycloalkyl, phenyl, aromatic or aryl, heteroaryl (5-6 membered ring), substituted aromatic or aryl, substituted heteroaryl (5-6 membered ring); Alternatively, when R1 is heteroaryl, R1 is preferably a 5- or 6-membered heteroaryl selected from the group consisting of pyrazolyl, triazolyl, oxazolyl, thiazolyl, thiophenyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl; wherein said aromatic, aryl or heteroaryl is unsubstituted, mono- or di-substituted; wherein the substituents are independently: (C 1~4 ) alkyl, (C 1~4 ) alkoxy, halogen, (C 1~3 ) fluoroalkyl, (C1~3 ) fluoroalkoxy and (C 3~7 ) cycloalkyl; R2, R3, and R4 are independently H, halogen (F, Cl, Br, etc.), alkyl, substituted alkyl, (C 1~4 ) alkyl, (C 1~4 ) alkoxy, (C 1~3 ) fluoroalkyl, (C 1~3 ) fluoroalkoxy and (C 3~7 ) cycloalkyl; wherein each of R2, R3, and R4 is independently and optionally substituted at each substitutable position with up to three independently selected substituents of one, two, or all of R2, R3, and R4; R5 is H, F, CH3, alkyl, substituted alkyl, (C 1~3 ) fluoroalkyl, cycloalkyl, and R5 is substituted at the carbon bearing Y, Z1, and Z2, where R5' is defined herein; R5' is an aromatic or aryl, heteroaryl (5-6 membered ring), substituted aromatic or aryl, substituted heteroaryl or fused two heteroaryl ring systems (5-6 membered ring); wherein said aromatic, aryl or heteroaryl is unsubstituted, mono- or di- or tri-substituted; wherein the substituents are independently: (C 1~4 ) alkyl, (C 1~4 ) alkoxy, halogen, (C 1~3 ) fluoroalkyl, (C 1~3 ) fluoroalkoxy, (C 3~7 ) cycloalkyl, (C 3~7 ) heterocycloalkyl; R6 is H, F, CH3, alkyl, substituted alkyl, (C 1~3 ) fluoroalkyl, cycloalkyl, and R6 is (C 1~3 ) R as alkyl to form a cyclic structure of alkyl bridge 10 or R11 connected to either of the following; R7 is H, F, CH3, alkyl, substituted alkyl, (C 1~3 ) fluoroalkyl, cycloalkyl, and R7 is substituted at the carbon bearing Y, Z1, and Z2, where R5' is defined herein; R8 is H, F, CH3, alkyl, substituted alkyl, (C 1~3 ) fluoroalkyl, cycloalkyl, and R8 is (C 1~3 ) R as alkyl to form a cyclic structure of alkyl bridge 10 , R 11 or R 12 connected to either of the following; R9 is H, F, CH3, alkyl, substituted alkyl, (C 1~3 ) fluoroalkyl, cycloalkyl, and R9 is (C 1~3 ) R6 or R as alkyl forming the cyclic structure of the alkyl bridge 12 connected to either of the following; R 10 is H, F, CH3, alkyl, substituted alkyl, (C 1~3 ) fluoroalkyl, cycloalkyl, or R 10 (C 1~3 ) R6 or R as alkyl forming the cyclic structure of the alkyl bridge 11 is connected to; R 11 is H, F, CH3, alkyl, substituted alkyl, (C 1~3 ) fluoroalkyl, cycloalkyl, or R 11 (C 1~3 ) linked to R6 as an alkyl forming a cyclic structure of the alkyl bridge; R 12 is H, F, CH3, alkyl, substituted alkyl, (C 1~3 ) fluoroalkyl, cycloalkyl, or R 12 (C 1~3 ) linked to R9 as an alkyl forming a cyclic structure of the alkyl bridge; X may be empty (e.g., to provide a five-membered pyrrolidine ring) or may be CH2, O, CR a R b (where R a and R b is alkyl, cycloalkyl, or fluoroalkyl; Here, it is preferred that the carbon atom at position 2 of the piperidine or pyrrolidine has an absolute (S) configuration; In contrast, the carbon atom at position 2 of the morpholine ring is preferably in the absolute (R) configuration (when X is O, i.e., oxygen); Y is either empty (R5' is directly connected to the carbon bearing the Z1 and Z2 groups) or O, NH, CH2OR5', CH2, NR a (where R a is alkyl, cycloalkyl, or heteroalkyl; Alternatively, Y may be selected as a preferred linker and be a 5- or 6-membered heteroaryl selected from the group consisting of pyrrolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, oxadiazolyl; and Z1 and Z2 are H, F, (C 1~4 ) alkyl, (C 1~3 ) fluoroalkyl, (C 1~3 ) fluoroalkoxy, (C 2~7 ) cycloalkyl, or independently selected from one of these groups.

[0015] A further embodiment of the present disclosure relates to preferred compounds wherein the imidazole-fused 6-membered ring is preferably according to embodiment formula I-a3 or II-a3 herein, where embodiment formulas I-a3 and II-a3 are respectively: [ka] where R1 is selected from the group consisting of H, alkyl, alkoxy, cycloalkyl, phenyl, aromatic or aryl, heteroaryl (5-6 membered ring), substituted aromatic or aryl, substituted heteroaryl (5-6 membered ring); Alternatively, when R1 is heteroaryl, R1 is preferably a 5- or 6-membered heteroaryl selected from the group consisting of pyrazolyl, triazolyl, oxazolyl, thiazolyl, thiophenyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl; wherein said aromatic, aryl or heteroaryl is unsubstituted, mono- or di-substituted; wherein the substituents are independently: (C 1~4 ) alkyl, (C 1~4 ) alkoxy, halogen, (C 1~3 ) fluoroalkyl, (C 1~3 ) fluoroalkoxy and (C 3~7 ) cycloalkyl; R2, R3, and R4 are independently H, halogen (F, Cl, Br, etc.), alkyl, substituted alkyl, (C 1~4 ) alkyl, (C 1~4 ) alkoxy, (C 1~3 ) fluoroalkyl, (C 1~3 ) fluoroalkoxy and (C 3~7 ) cycloalkyl; wherein each of R2, R3, and R4 is independently and optionally substituted at each substitutable position with up to three independently selected substituents of one, two, or all of R2, R3, and R4; R5 is H, F, CH3, alkyl, substituted alkyl, (C 1~3 ) fluoroalkyl, cycloalkyl, and R5 is substituted at the carbon bearing Y, Z1, and Z2, where R5' is defined herein; R5' is an aromatic or aryl, heteroaryl (5-6 membered ring), substituted aromatic or aryl, substituted heteroaryl or fused two heteroaryl ring systems (5-6 membered ring); wherein said aromatic, aryl or heteroaryl is unsubstituted, mono- or di- or tri-substituted; wherein the substituents are independently: (C 1~4 ) alkyl, (C 1~4 ) alkoxy, halogen, (C 1~3 ) fluoroalkyl, (C 1~3 ) fluoroalkoxy, (C 3~7 ) cycloalkyl, (C 3~7 ) heterocycloalkyl; R6 is H, F, CH3, alkyl, substituted alkyl, (C 1~3 ) fluoroalkyl, cycloalkyl, and R6 is (C 1~3 ) R as alkyl to form a cyclic structure of alkyl bridge 10 or R 11 connected to either of the following; R7 is H, F, CH3, alkyl, substituted alkyl, (C 1~3 ) fluoroalkyl, cycloalkyl, and R7 is substituted at the carbon bearing Y, Z1, and Z2, where R5' is defined herein; R8 is H, F, CH3, alkyl, substituted alkyl, (C 1~3 ) fluoroalkyl, cycloalkyl, and R8 is (C 1~3 ) R as alkyl to form a cyclic structure of alkyl bridge 10 , R 11 or R 12 connected to either of the following; R9 is H, F, CH3, alkyl, substituted alkyl, (C 1~3 ) fluoroalkyl, cycloalkyl, and R9 is (C 1~3 ) R6 or R as alkyl forming the cyclic structure of the alkyl bridge 12 connected to either of the following; R 10is H, F, CH3, alkyl, substituted alkyl, (C 1~3 ) fluoroalkyl, cycloalkyl, or R 10 (C 1~3 ) R6 or R as alkyl forming the cyclic structure of the alkyl bridge 11 is connected to; R 11 is H, F, CH3, alkyl, substituted alkyl, (C 1~3 ) fluoroalkyl, cycloalkyl, or R 11 (C 1~3 ) linked to R6 as an alkyl forming a cyclic structure of the alkyl bridge; R 12 is H, F, CH3, alkyl, substituted alkyl, (C 1~3 ) fluoroalkyl, cycloalkyl, or R 12 (C 1~3 ) linked to R9 as an alkyl forming a cyclic structure of the alkyl bridge; X may be empty (e.g., to provide a five-membered pyrrolidine ring) or may be CH2, O, CR a R b (where R a and R b is alkyl, cycloalkyl, or fluoroalkyl; Here, it is preferred that the carbon atom at position 2 of the piperidine or pyrrolidine has an absolute (S) configuration; In contrast, the carbon atom at position 2 of the morpholine ring is preferably in the absolute (R) configuration (when X is O, i.e., oxygen); Y is either empty (R5' is directly connected to the carbon bearing the Z1 and Z2 groups) or O, NH, CH2OR5', CH2, NR a (where R a is alkyl, cycloalkyl, or heteroalkyl); Alternatively, Y may be selected as a preferred linker and be a 5- or 6-membered heteroaryl selected from the group consisting of pyrrolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, oxadiazolyl; and Z1 and Z2 are H, F, (C 1~4 ) alkyl, (C 1~3 ) fluoroalkyl, (C 1~3 ) fluoroalkoxy, (C 2~7 ) cycloalkyl, or independently selected from one of these groups.

[0016] A further embodiment of the present disclosure relates to preferred compounds wherein the pyrazole-fused 6-membered ring is preferably according to the embodiment of formula I-b1 or II-b1 herein, where formula I-b1 and II-b1 are, respectively: [ka] where R1 is selected from the group consisting of H, alkyl, alkoxy, cycloalkyl, phenyl, aromatic or aryl, heteroaryl (5-6 membered ring), substituted aromatic or aryl, substituted heteroaryl (5-6 membered ring); Alternatively, when R1 is heteroaryl, R1 is preferably a 5- or 6-membered heteroaryl selected from the group consisting of pyrazolyl, triazolyl, oxazolyl, thiazolyl, thiophenyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl; wherein said aromatic, aryl or heteroaryl is unsubstituted, mono- or di-substituted; wherein the substituents are independently: (C 1~4 ) alkyl, (C 1~4 ) alkoxy, halogen, (C 1~3 ) fluoroalkyl, (C 1~3 ) fluoroalkoxy and (C 3~7 ) cycloalkyl; R2, R3, and R4 are independently H, halogen (F, Cl, Br, etc.), alkyl, substituted alkyl, (C 1~4 ) alkyl, (C 1~4 ) alkoxy, (C 1~3 ) fluoroalkyl, (C1~3 ) fluoroalkoxy and (C 3~7 ) cycloalkyl; wherein each of R2, R3, and R4 is independently and optionally substituted at each substitutable position with up to three independently selected substituents of one, two, or all of R2, R3, and R4; R5 is H, F, CH3, alkyl, substituted alkyl, (C 1~3 ) fluoroalkyl, cycloalkyl, and R5 is substituted at the carbon bearing Y, Z1, and Z2, where R5' is defined herein; R5' is an aromatic or aryl, heteroaryl (5-6 membered ring), substituted aromatic or aryl, substituted heteroaryl or fused two heteroaryl ring systems (5-6 membered ring); wherein said aromatic, aryl or heteroaryl is unsubstituted, mono- or di- or tri-substituted; wherein the substituents are independently: (C 1~4 ) alkyl, (C 1~4 ) alkoxy, halogen, (C 1~3 ) fluoroalkyl, (C 1~3 ) fluoroalkoxy, (C 3~7 ) cycloalkyl, (C 3~7 ) heterocycloalkyl; R6 is H, F, CH3, alkyl, substituted alkyl, (C 1~3 ) fluoroalkyl, cycloalkyl, and R6 is (C 1~3 ) R as alkyl to form a cyclic structure of alkyl bridge 10 or R 11 connected to either of the following; R7 is H, F, CH3, alkyl, substituted alkyl, (C 1~3 ) fluoroalkyl, cycloalkyl, and R7 is substituted at the carbon bearing Y, Z1, and Z2, where R5' is defined herein; R8 is H, F, CH3, alkyl, substituted alkyl, (C1~3 ) fluoroalkyl, cycloalkyl, and R8 is (C 1~3 ) R as alkyl to form a cyclic structure of alkyl bridge 10 , R 11 or R 12 connected to either of the following; R9 is H, F, CH3, alkyl, substituted alkyl, (C 1~3 ) fluoroalkyl, cycloalkyl, and R9 is (C 1~3 ) R6 or R as alkyl forming the cyclic structure of the alkyl bridge 12 connected to either of the following; R 10 is H, F, CH3, alkyl, substituted alkyl, (C 1~3 ) fluoroalkyl, cycloalkyl, or R 10 (C 1~3 ) R6 or R as alkyl forming the cyclic structure of the alkyl bridge 11 is connected to; R 11 is H, F, CH3, alkyl, substituted alkyl, (C 1~3 ) fluoroalkyl, cycloalkyl, or R 11 (C 1~3 ) linked to R6 as an alkyl forming a cyclic structure of the alkyl bridge; R 12 is H, F, CH3, alkyl, substituted alkyl, (C 1~3 ) fluoroalkyl, cycloalkyl, or R 12 (C 1~3 ) linked to R9 as an alkyl forming a cyclic structure of the alkyl bridge; X may be empty (e.g., to provide a five-membered pyrrolidine ring) or may be CH2, O, CR a R b (where R a and R b is alkyl, cycloalkyl, or fluoroalkyl; Here, it is preferred that the carbon atom at position 2 of the piperidine or pyrrolidine has an absolute (S) configuration; In contrast, the carbon atom at position 2 of the morpholine ring is preferably in the absolute (R) configuration (when X is O, i.e., oxygen); Y is either empty (R5' is directly connected to the carbon bearing the Z1 and Z2 groups) or O, NH, CH2OR5', CH2, NR a (where R a is alkyl, cycloalkyl, or heteroalkyl; Alternatively, Y may be selected as a preferred linker and be a 5- or 6-membered heteroaryl selected from the group consisting of pyrrolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, oxadiazolyl; and Z1 and Z2 are H, F, (C 1~4 ) alkyl, (C 1~3 ) fluoroalkyl, (C 1~3 ) fluoroalkoxy, (C 2~7 ) cycloalkyl, or independently; wherein the preferred groups are: M = carbon, CH, CHR2, CHR3, CR2R3, CR2, CR3, CR4, and N.

[0017] A further embodiment of the present disclosure relates to preferred compounds wherein the pyrazole-fused 6-membered ring is preferably according to the embodiment of formula I-b2 or II-b2 herein, where formula I-b2 and II-b2 are, respectively: [ka] where R1 is selected from the group consisting of H, alkyl, alkoxy, cycloalkyl, phenyl, aromatic or aryl, heteroaryl (5-6 membered ring), substituted aromatic or aryl, substituted heteroaryl (5-6 membered ring); Alternatively, when R1 is heteroaryl, R1 is preferably a 5- or 6-membered heteroaryl selected from the group consisting of pyrazolyl, triazolyl, oxazolyl, thiazolyl, thiophenyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl; wherein said aromatic, aryl or heteroaryl is unsubstituted, mono- or di-substituted; wherein the substituents are independently: (C 1~4 ) alkyl, (C 1~4 ) alkoxy, halogen, (C 1~3 ) fluoroalkyl, (C 1~3 ) fluoroalkoxy and (C 3~7 ) cycloalkyl; R2, R3, and R4 are independently H, halogen (F, Cl, Br, etc.), alkyl, substituted alkyl, (C 1~4 ) alkyl, (C 1~4 ) alkoxy, (C 1~3 ) fluoroalkyl, (C 1~3 ) fluoroalkoxy and (C 3~7 ) cycloalkyl; wherein each of R2, R3, and R4 is independently and optionally substituted at each substitutable position with up to three independently selected substituents of one, two, or all of R2, R3, and R4; R5 is H, F, CH3, alkyl, substituted alkyl, (C 1~3 ) fluoroalkyl, cycloalkyl, and R5 is substituted at the carbon bearing Y, Z1, and Z2, where R5' is defined herein; R5' is an aromatic or aryl, heteroaryl (5-6 membered ring), substituted aromatic or aryl, substituted heteroaryl or fused two heteroaryl ring systems (5-6 membered ring); wherein said aromatic, aryl or heteroaryl is unsubstituted, mono- or di- or tri-substituted; wherein the substituents are independently: (C 1~4) alkyl, (C 1~4 ) alkoxy, halogen, (C 1~3 ) fluoroalkyl, (C 1~3 ) fluoroalkoxy, (C 3~7 ) cycloalkyl, (C 3~7 ) heterocycloalkyl; R6 is H, F, CH3, alkyl, substituted alkyl, (C 1~3 ) fluoroalkyl, cycloalkyl, and R6 is (C 1~3 ) R as alkyl to form a cyclic structure of alkyl bridge 10 or R 11 connected to either of the following; R7 is H, F, CH3, alkyl, substituted alkyl, (C 1~3 ) fluoroalkyl, cycloalkyl, and R7 is substituted at the carbon bearing Y, Z1, and Z2, where R5' is defined herein; R8 is H, F, CH3, alkyl, substituted alkyl, (C 1~3 ) fluoroalkyl, cycloalkyl, and R8 is (C 1~3 ) R as alkyl to form a cyclic structure of alkyl bridge 10 , R 11 or R 12 connected to either of the following; R9 is H, F, CH3, alkyl, substituted alkyl, (C 1~3 ) fluoroalkyl, cycloalkyl, and R9 is (C 1~3 ) R6 or R as alkyl forming the cyclic structure of the alkyl bridge 12 connected to either of the following; R 10 is H, F, CH3, alkyl, substituted alkyl, (C 1~3 ) fluoroalkyl, cycloalkyl, or R 10 (C 1~3 ) R6 or R as alkyl forming the cyclic structure of the alkyl bridge 11 is connected to; R 11 is H, F, CH3, alkyl, substituted alkyl, (C1~3 ) fluoroalkyl, cycloalkyl, or R 11 (C 1~3 ) linked to R6 as an alkyl forming a cyclic structure of the alkyl bridge; R 12 is H, F, CH3, alkyl, substituted alkyl, (C 1~3 ) fluoroalkyl, cycloalkyl, or R 12 (C 1~3 ) linked to R9 as an alkyl forming a cyclic structure of the alkyl bridge; X may be empty (e.g., to provide a five-membered pyrrolidine ring) or may be CH2, O, CR a R b (where R a and R b is alkyl, cycloalkyl, or fluoroalkyl; Here, it is preferred that the carbon atom at position 2 of the piperidine or pyrrolidine has an absolute (S) configuration; In contrast, the carbon atom at position 2 of the morpholine ring is preferably in the absolute (R) configuration (when X is O, i.e., oxygen); Y is either empty (R5' is directly connected to the carbon bearing the Z1 and Z2 groups) or O, NH, CH2OR5', CH2, NR a (where R a is alkyl, cycloalkyl, or heteroalkyl; Alternatively, Y may be selected as a preferred linker and be a 5- or 6-membered heteroaryl selected from the group consisting of pyrrolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, oxadiazolyl; and Z1 and Z2 are H, F, (C 1~4 ) alkyl, (C 1~3 ) fluoroalkyl, (C 1~3 ) fluoroalkoxy, (C 2~7 ) cycloalkyl, or independently selected from one of these groups.

[0018] A further embodiment of the present disclosure relates to preferred compounds wherein the pyrazole-fused 6-membered ring is preferably according to the embodiment of formula I-b3 or II-b3 herein, where formula I-b3 and II-b3 are, respectively: [ka] where R1 is selected from the group consisting of H, alkyl, alkoxy, cycloalkyl, phenyl, aromatic or aryl, heteroaryl (5-6 membered ring), substituted aromatic or aryl, substituted heteroaryl (5-6 membered ring); Alternatively, when R1 is heteroaryl, R1 is preferably a 5- or 6-membered heteroaryl selected from the group consisting of pyrazolyl, triazolyl, oxazolyl, thiazolyl, thiophenyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl; wherein said aromatic, aryl or heteroaryl is unsubstituted, mono- or di-substituted; wherein the substituents are independently: (C 1~4 ) alkyl, (C 1~4 ) alkoxy, halogen, (C 1~3 ) fluoroalkyl, (C 1~3 ) fluoroalkoxy and (C 3~7 ) cycloalkyl; R2, R3, and R4 are independently H, halogen (F, Cl, Br, etc.), alkyl, substituted alkyl, (C 1~4 ) alkyl, (C 1~4 ) alkoxy, (C 1~3 ) fluoroalkyl, (C 1~3 ) fluoroalkoxy and (C 3~7 ) cycloalkyl; wherein each of R2, R3, and R4 is independently and optionally substituted at each substitutable position with up to three independently selected substituents of one, two, or all of R2, R3, and R4; R5 is H, F, CH3, alkyl, substituted alkyl, (C 1~3 ) fluoroalkyl, cycloalkyl, and R5 is substituted at the carbon bearing Y, Z1, and Z2, where R5' is defined herein; R5' is an aromatic or aryl, heteroaryl (5-6 membered ring), substituted aromatic or aryl, substituted heteroaryl or fused two heteroaryl ring systems (5-6 membered ring); wherein said aromatic, aryl or heteroaryl is unsubstituted, mono- or di- or tri-substituted; wherein the substituents are independently: (C 1~4 ) alkyl, (C 1~4 ) alkoxy, halogen, (C 1~3 ) fluoroalkyl, (C 1~3 ) fluoroalkoxy, (C 3~7 ) cycloalkyl, (C 3~7 ) heterocycloalkyl; R6 is H, F, CH3, alkyl, substituted alkyl, (C 1~3 ) fluoroalkyl, cycloalkyl, and R6 is (C 1~3 ) R as alkyl to form a cyclic structure of alkyl bridge 10 or R 11 connected to either of the following; R7 is H, F, CH3, alkyl, substituted alkyl, (C 1~3 ) fluoroalkyl, cycloalkyl, and R7 is substituted at the carbon bearing Y, Z1, and Z2, where R5' is defined herein; R8 is H, F, CH3, alkyl, substituted alkyl, (C 1~3 ) fluoroalkyl, cycloalkyl, and R8 is (C 1~3 ) R as alkyl to form a cyclic structure of alkyl bridge 10 , R 11 or R 12 connected to either of the following; R9 is H, F, CH3, alkyl, substituted alkyl, (C 1~3) fluoroalkyl, cycloalkyl, and R9 is (C 1~3 ) R6 or R as alkyl forming the cyclic structure of the alkyl bridge 12 connected to either of the following; R 10 is H, F, CH3, alkyl, substituted alkyl, (C 1~3 ) fluoroalkyl, cycloalkyl, or R 10 (C 1~3 ) R6 or R as alkyl forming the cyclic structure of the alkyl bridge 11 is connected to; R 11 is H, F, CH3, alkyl, substituted alkyl, (C 1~3 ) fluoroalkyl, cycloalkyl, or R 11 (C 1~3 ) linked to R6 as an alkyl forming a cyclic structure of the alkyl bridge; R 12 is H, F, CH3, alkyl, substituted alkyl, (C 1~3 ) fluoroalkyl, cycloalkyl, or R 12 (C 1~3 ) linked to R9 as an alkyl forming a cyclic structure of the alkyl bridge; X may be empty (e.g., to provide a five-membered pyrrolidine ring) or may be CH2, O, CR a R b (where R a and R b is alkyl, cycloalkyl, or fluoroalkyl; Here, it is preferred that the carbon atom at position 2 of the piperidine or pyrrolidine has an absolute (S) configuration; In contrast, the carbon atom at position 2 of the morpholine ring is preferably in the absolute (R) configuration (when X is O, i.e., oxygen); Y is either empty (R5' is directly connected to the carbon bearing the Z1 and Z2 groups) or O, NH, CH2OR5', CH2, NR a (where R a is alkyl, cycloalkyl, or heteroalkyl; Alternatively, Y may be selected as a preferred linker and be a 5- or 6-membered heteroaryl selected from the group consisting of pyrrolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, oxadiazolyl; and Z1 and Z2 are H, F, (C 1~4 ) alkyl, (C 1~3 ) fluoroalkyl, (C 1~3 ) fluoroalkoxy, (C 2~7 ) cycloalkyl, or independently selected from one of these groups.

[0019] In a more specific (i.e., preferred) embodiment of the present disclosure, the present disclosure relates to preferred compounds whose stereocenters and main backbone rings are as shown in the exemplary formulas according to the embodiments of formula I-a4, I-a5, I-a6, II-a4, II-a5, or II-a6 herein, wherein formula I-a4, I-a5, I-a6, II-a4, II-a5, and II-a6 are, respectively: [ka] where R1 is selected from the group consisting of H, alkyl, alkoxy, cycloalkyl, phenyl, aromatic or aryl, heteroaryl (5-6 membered ring), substituted aromatic or aryl, substituted heteroaryl (5-6 membered ring); Alternatively, when R1 is heteroaryl, R1 is preferably a 5- or 6-membered heteroaryl selected from the group consisting of pyrazolyl, triazolyl, oxazolyl, thiazolyl, thiophenyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl; wherein said aromatic, aryl or heteroaryl is unsubstituted, mono- or di-substituted; wherein the substituents are independently: (C 1~4 ) alkyl, (C 1~4 ) alkoxy, halogen, (C 1~3 ) fluoroalkyl, (C 1~3) fluoroalkoxy and (C 3~7 ) cycloalkyl; R2, R3, and R4 are independently H, halogen (F, Cl, Br, etc.), alkyl, substituted alkyl, (C 1~4 ) alkyl, (C 1~4 ) alkoxy, (C 1~3 ) fluoroalkyl, (C 1~3 ) fluoroalkoxy and (C 3~7 ) cycloalkyl; wherein each of R2, R3, and R4 is independently and optionally substituted at each substitutable position with up to three independently selected substituents of one, two, or all of R2, R3, and R4; R5 is H or substituted at a carbon bearing Y, Z1, and Z2, where R5' is defined herein; R5' is an aromatic or aryl, heteroaryl (5-6 membered ring), substituted aromatic or aryl, substituted heteroaryl or fused two heteroaryl ring systems (5-6 membered ring); wherein said aromatic, aryl or heteroaryl is unsubstituted, mono- or di- or tri-substituted; wherein the substituents are independently: (C 1~4 ) alkyl, (C 1~4 ) alkoxy, halogen, (C 1~3 ) fluoroalkyl, (C 1~3 ) fluoroalkoxy, (C 3~7 ) cycloalkyl, (C 3~7 ) heterocycloalkyl; R6 is H, F, CH3, alkyl, substituted alkyl, (C 1~3 ) fluoroalkyl, cycloalkyl, and R6 is (C 1~3 ) R as alkyl to form a cyclic structure of alkyl bridge 10 or R 11 connected to either of the following; R7 is H or substituted at a carbon bearing Y, Z1, and Z2, where R5' is defined herein; R8 is H, F, CH3, alkyl, substituted alkyl, (C 1~3 ) fluoroalkyl, cycloalkyl, and R8 is (C 1~3 ) R as alkyl to form a cyclic structure of alkyl bridge 10 , R 11 or R 12 connected to either of the following; R9 is H, F, CH3, alkyl, substituted alkyl, (C 1~3 ) fluoroalkyl, cycloalkyl, and R9 is (C 1~3 ) R6 or R as alkyl forming the cyclic structure of the alkyl bridge 12 connected to either of the following; R 10 is H, F, CH3, alkyl, substituted alkyl, (C 1~3 ) fluoroalkyl, cycloalkyl, or R 10 (C 1~3 ) R6 or R as alkyl forming the cyclic structure of the alkyl bridge 11 is connected to; R 11 is H, F, CH3, alkyl, substituted alkyl, (C 1~3 ) fluoroalkyl, cycloalkyl, or R 11 (C 1~3 ) linked to R6 as an alkyl forming a cyclic structure of the alkyl bridge; R 12 is H, F, CH3, alkyl, substituted alkyl, (C 1~3 ) fluoroalkyl, cycloalkyl, or R 12 (C 1~3 ) linked to R9 as an alkyl forming a cyclic structure of the alkyl bridge; X may be empty (e.g., to provide a five-membered pyrrolidine ring) or may be CH2, O, CR a R b (where R a and R bis alkyl, cycloalkyl, or fluoroalkyl; Here, it is preferred that the carbon atom at position 2 of the piperidine or pyrrolidine has an absolute (S) configuration; In contrast, the carbon atom at position 2 of the morpholine ring is preferably in the absolute (R) configuration (when X is O, i.e., oxygen); Y is either empty (R5' is directly connected to the carbon bearing the Z1 and Z2 groups) or O, NH, CH2OR5', CH2, NR a (where R a is alkyl, cycloalkyl, or heteroalkyl); Alternatively, Y may be selected as a preferred linker and be a 5- or 6-membered heteroaryl selected from the group consisting of pyrrolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, oxadiazolyl; Z1 and Z2 are H, F, (C 1~4 ) alkyl, (C 1~3 ) fluoroalkyl, (C 1~3 ) fluoroalkoxy, (C 2~7 ) cycloalkyl or independently selected from one of these groups; and L is carbon, CH, CHR, CHR, CR, CR, CR, CR, and N.

[0020] In a more specific (i.e., preferred) embodiment of the present disclosure, the present disclosure relates to preferred compounds whose stereocenters and main backbone rings are as shown in the exemplary formulas according to the embodiments of formula I-b4, I-b5, I-b6, II-b4, II-b5, or II-b6 herein, wherein formula I-b4, I-b5, I-b6, II-b4, II-b5, and II-b6 are, respectively: [ka] where R1 is selected from the group consisting of H, alkyl, alkoxy, cycloalkyl, phenyl, aromatic or aryl, heteroaryl (5-6 membered ring), substituted aromatic or aryl, substituted heteroaryl (5-6 membered ring); or, when R1 is heteroaryl, R1 is preferably a 5- or 6-membered heteroaryl selected from the group consisting of pyrazolyl, triazolyl, oxazolyl, thiazolyl, thiophenyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl; wherein said aromatic, aryl or heteroaryl is unsubstituted, mono- or di-substituted; wherein the substituents are independently: (C 1~4 ) alkyl, (C 1~4 ) alkoxy, halogen, (C 1~3 ) fluoroalkyl, (C 1~3 ) fluoroalkoxy and (C 3~7 ) cycloalkyl; R2, R3, and R4 are independently H, halogen (F, Cl, Br, etc.), alkyl, substituted alkyl, (C 1~4 ) alkyl, (C 1~4 ) alkoxy, (C 1~3 ) fluoroalkyl, (C 1~3 ) fluoroalkoxy and (C 3~7 ) cycloalkyl; wherein each of R2, R3, and R4 is independently and optionally substituted at each substitutable position with up to three independently selected substituents of one, two, or all of R2, R3, and R4; R5 is H or substituted at a carbon bearing Y, Z1, and Z2, where R5' is defined herein; R5' is an aromatic or aryl, heteroaryl (5-6 membered ring), substituted aromatic or aryl, substituted heteroaryl or fused two heteroaryl ring systems (5-6 membered ring); wherein said aromatic, aryl or heteroaryl is unsubstituted, mono- or di- or tri-substituted; wherein the substituents are independently: (C 1~4 ) alkyl, (C 1~4 ) alkoxy, halogen, (C 1~3 ) fluoroalkyl, (C 1~3 ) fluoroalkoxy, (C 3~7 ) cycloalkyl, (C 3~7 ) heterocycloalkyl; R6 is H, F, CH3, alkyl, substituted alkyl, (C 1~3 ) fluoroalkyl, cycloalkyl, and R6 is (C 1~3 ) R as alkyl to form a cyclic structure of alkyl bridge 10 or R 11 connected to either of the following; R7 is H or substituted at a carbon bearing Y, Z1, and Z2, where R5' is defined herein; R8 is H, F, CH3, alkyl, substituted alkyl, (C 1~3 ) fluoroalkyl, cycloalkyl, and R8 is (C 1~3 ) R as alkyl to form a cyclic structure of alkyl bridge 10 , R 11 or R 12 connected to either of the following; R9 is H, F, CH3, alkyl, substituted alkyl, (C 1~3 ) fluoroalkyl, cycloalkyl, and R9 is (C 1~3 ) R6 or R as alkyl forming the cyclic structure of the alkyl bridge 12 connected to either of the following; R 10 is H, F, CH3, alkyl, substituted alkyl, (C 1~3 ) fluoroalkyl, cycloalkyl, or R 10 (C 1~3 ) R6 or R as alkyl forming the cyclic structure of the alkyl bridge 11 is connected to; R11 is H, F, CH3, alkyl, substituted alkyl, (C 1~3 ) fluoroalkyl, cycloalkyl, or R 11 (C 1~3 ) linked to R6 as an alkyl forming a cyclic structure of the alkyl bridge; R 12 is H, F, CH3, alkyl, substituted alkyl, (C 1~3 ) fluoroalkyl, cycloalkyl, or R 12 (C 1~3 ) linked to R9 as an alkyl forming a cyclic structure of the alkyl bridge; X may be empty (e.g., to provide a five-membered pyrrolidine ring) or may be CH2, O, CR a R b (where R a and R b is alkyl, cycloalkyl, or fluoroalkyl; Here, it is preferred that the carbon atom at position 2 of the piperidine or pyrrolidine has an absolute (S) configuration; In contrast, the carbon atom at position 2 of the morpholine ring is preferably in the absolute (R) configuration (when X is O, i.e., oxygen); Y is either empty (R5' is directly connected to the carbon bearing the Z1 and Z2 groups) or O, NH, CH2OR5', CH2, NR a (where R a is alkyl, cycloalkyl, or heteroalkyl; Alternatively, Y may be selected as a preferred linker and be a 5- or 6-membered heteroaryl selected from the group consisting of pyrrolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, oxadiazolyl; and Z1 and Z2 are H, F, (C 1~4 ) alkyl, (C 1~3 ) fluoroalkyl, (C 1~3 ) fluoroalkoxy, (C 2~7 ) cycloalkyl or independently selected from one of these groups; wherein the preferred groups are: M = carbon, CH, CHR2, CHR3, CR2R3, CR2, CR3, CR4, and N.

[0021] Examples of preferred compounds included in Formula I, II, II-a, and / or II-b, and sub-formulas included within the main formulas, and preferred embodiments thereof, are shown in Table 1 below.

[0022] Preferred compounds of the present disclosure are those shown in Examples 1-263 below. These compounds are shown in the Examples section of this disclosure and below. In the event that any of the compound example numbers and / or compound structures shown in this Table 1 conflict with those shown in the actual Examples section (Table 3), the numbering and / or structure in Table 3 shall control.

[0023] [Table 1] TIFF2025530768000014.tif248158TIFF2025530768000015.tif219158TIFF20255307680 00016.tif222158TIFF2025530768000017.tif222158TIFF2025530768000018.tif223158 TIFF2025530768000019.tif242158TIFF2025530768000020.tif232158TIFF20255307680 00021.tif248158JPEG2025530768000022.jpg229158TIFF2025530768000023.tif228158 JPEG2025530768000024.jpg248158JPEG2025530768000025.jpg243158TIFF20255307680 00026.tif228158JPEG2025530768000027.jpg228158JPEG2025530768000028.jpg228158 JPEG2025530768000029.jpg228158JPEG2025530768000030.jpg227158JPEG20255307680 00031.jpg248158JPEG2025530768000032.jpg249158TIFF2025530768000033.tif189158

[0024] More preferred compounds of the present disclosure are the compounds of Examples 4, 6, 7, 8, 10, 12, 13, 20, 22, 24, 25-29, 34, 40, 42-50, 53-64, 66-69, 73, 75, 78, 80, 89, 90, 92, 94, 95, 97, 107, 111, 112, 117-119, 122-142, 147-151, 156, 158, 171-183, 185-198, 201-203, 205, 207, 208, 210-214, 223, and 224 shown below.

[0025] The most preferred compounds of the present disclosure are compounds of Examples 53, 55, 66, 95, 112, 118, 119, 122, 123, 124, 129, 130, 131, 134, 135, 138, 139, 140, 141, 142, 147, 148, 156, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 191, 195, 203, 205, 211, 223, and 224 shown below.

[0026] Any embodiment shown herein is also intended to represent unlabeled and isotopically labeled forms of the compound, unless otherwise specified. Isotopically labeled compounds have the structure of the chemical formula shown herein, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine (H, H, C, C, C, N, F, P, P, S, Cl, I, etc.). The present disclosure includes various isotopically labeled compounds as defined herein, for example, compounds into which radioactive isotopes (H, C, and C, etc.) are incorporated. Such isotopically labeled compounds are useful for metabolic studies (preferably with C), kinetic studies (e.g., with H or H), detection or imaging techniques (including drug or substrate tissue distribution assays) such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT), or radioisotope treatment of patients. In particular, F- or labeled compounds may be particularly preferred for PET or SPECT studies. The isotopically labeled compounds and prodrugs of the present disclosure can generally be prepared by carrying out the procedures disclosed in the schemes or in the Examples and preparation methods described below, substituting readily available isotopically labeled reagents for non-isotopically labeled reagents.

[0027] Many of the compounds useful in the methods and compositions of the present disclosure possess at least one stereocenter in their structure. This stereocenter may exist in the R or S configuration, and the R and S designations are used in accordance with the rules set forth in Pure Appl. Chem. (1976), 45, 11-30. The present disclosure also relates to all stereoisomeric forms, such as enantiomeric and diastereoisomeric forms of the compounds, or mixtures thereof, including all possible mixtures of stereoisomers. See, for example, WO 01 / 062726. Furthermore, multiple substituents on a piperidinyl or pyrrolidinyl ring may be in either a cis or trans relationship to each other with respect to the plane of the piperidinyl or pyrrolidinyl ring. Such geometric isomeric forms, although not explicitly depicted in the chemical formulas set forth herein, are intended to be included within the scope of the present disclosure. With respect to the methods and compositions of the present disclosure, unless a particular isomeric form is specifically referred to, a reference to a single compound or compounds is intended to include the compound in each of its possible isomeric forms and mixtures thereof.

[0028] Pharmaceutically acceptable salts as described herein refer to chemical substances or compounds according to the present disclosure in the form of therapeutically active, non-toxic base and acid salts of the compounds. Acid addition salt forms of compounds that exist in their free form as bases can be obtained by treating the free base form with a suitable acid, such as inorganic acids such as hydrogen halides (hydrochloric or hydrobromic acid), sulfuric acid, nitric acid, phosphoric acid, etc.; or organic acids, such as acetic acid, hydroxyacetic acid, propanoic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclic acids, salicylic acid, p-aminosalicylic acid, pamoic acid, and the like (see, e.g., WO 01 / 062726, U.S. Patent No. 8,492,416 B2, U.S. Patent No. 2017 / 0022208 A1, and U.S. Patent No. 2017 / 0253603 A2).

[0029] Compounds containing acidic protons can be converted into their therapeutically effective non-toxic base addition salt forms, such as metal salts or amine salts, by treating with appropriate organic and inorganic bases. Suitable base salt forms include, for example, ammonium salts, alkali and alkaline earth metal salts (e.g., lithium salts, sodium salts, potassium salts, magnesium salts, calcium salts, etc.), salts with organic bases, and salts with amino acids (e.g., arginine, lysine, etc.). Conversely, the salt forms can be converted into free forms by treating with appropriate bases or acids. Compounds and their salts may be in the form of solvates within the scope of the present disclosure. Examples of such solvates include hydrates, alcoholates, etc.

[0030] It will be understood that throughout this specification, expressions such as "comprise" or its variations "comprises" or "comprising" are intended to include the stated integer (or component) or group of integers (or components), but not to exclude any other integer (or component) or group of integers (or components). The singular forms "a", "an", and "the" also include the plural unless the context clearly dictates otherwise. The term "including" is used to mean "including but not limited to", The terms "including" and "including but not limited to" are used synonymously. The term "substance addiction" or "substance abuse disorder" (SUD) can include addiction to any of a number of stimulants (e.g., including but not limited to, cocaine, methamphetamines, nicotine, etc.) or sedatives (e.g., including but not limited to, opioids, alcohol, etc.). As used herein, the term "chemical" refers to a compound (e.g., an organic compound or a mixture of compounds). Chemicals include, for example, chemicals that are known in terms of structure, and the orexin and / or kappa activity of such chemicals. Opioid antagonist / modulator activity may make them suitable as "therapeutic agents" in the methods and compositions of the present disclosure. When the term "=" is used to describe a substituent (e.g., R1), it is understood to mean "selected from the group consisting of." When the term "=" is used in reference to multiple possible substituents, it is understood to mean that each such possible substituent may be independently selected from the group listed thereafter (e.g., "Z1, Z2=" is intended to indicate "Z1 and Z2 are independently selected from the group consisting of (listed group)").

[0031] The term "aryl" as used herein means a monocyclic or bicyclic carbocyclic aromatic or aryl ring system. Phenyl is a non-limiting example of a monocyclic aromatic or aryl ring system (unless otherwise specified).

[0032] As used herein, the term "heteroaryl" refers to a monocyclic or bicyclic aromatic or aryl ring system having one to three heteroatoms or heteroatomic groups in each ring selected from O, N, NH, or S in a chemically stable arrangement. In such bicyclic aromatic or aryl ring system embodiments of "heteroaryl," both rings may be aromatic or aryl, and either or both rings may contain the heteroatom or heteroatom group. Examples of heteroaryl rings include 2-furanyl, 3-furanyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, benzimidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (e.g., 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (e.g., 5-tetrazolyl), triazolyl (e.g., 2-triazolyl), and 5-triazolyl), 2-thienyl, 3-thienyl, benzofuryl, benzothiophenyl, indolyl (e.g., 2-indolyl), pyrazolyl (e.g., 2-pyrazolyl), isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, purinyl, pyrazinyl, 1,3,5-triazinyl, quinolinyl (e.g., 2-quinolinyl, 3-quinolinyl, 4-quinolinyl), and isoquinolinyl (e.g., 1-isoquinolinyl, 3-isoquinolinyl, or 4-isoquinolinyl).

[0033] The term "cycloalkyl or cycloalkenyl" refers to a monocyclic or fused, or (C 1~3) refers to an alkyl-bridged bicyclic carbocyclic ring system that is neither aromatic nor aryl. The cycloalkenyl ring has one or more units of unsaturation. Preferred cycloalkyl or cycloalkenyl groups include groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, norbornyl, adamantyl, and decalinyl.

[0034] The compounds of the present disclosure also include prodrugs, analogs, or derivatives. The term "prodrug" is art-known and is intended to include compounds or chemicals that are converted to orexin antagonists and kappa opioid antagonists under physiological conditions. A common method for creating prodrugs is by selecting a moiety that is hydrolyzed or metabolized under physiological conditions to yield the desired compound or chemical. In other embodiments, the prodrug is converted to an orexin antagonist and / or kappa opioid antagonist (i.e., as an antagonist and / or modulator thereof) by the enzymatic activity of the host animal.

[0035] The present disclosure also includes isotopically labeled compounds, particularly H (deuterium) labeled compounds, for all chemical formulas; that is, the compounds are identical to any compound of the chemical formulas described herein, except that one or more atoms are replaced by atoms with the same atomic number but with an atomic mass different from the atomic mass normally found in nature.Isotopically labeled compounds of all chemical formulas, particularly H (deuterium) labeled compounds, and salts thereof, are within the scope of the present disclosure.Replacing hydrogen with a heavier isotope H (deuterium) can provide stronger metabolic stability, for example, extending in vivo half-life or reducing required doses; or reducing the inhibition of cytochrome P450 enzymes, for example, improving safety profiles.In another aspect of the embodiment of the present disclosure, compounds of all chemical formulas are not isotopically labeled.However, by using appropriate isotopic modifications of suitable reagents or starting materials, those skilled in the art can prepare isotopically labeled compounds of all chemical formulas according to the methods described herein below.

[0036] In some embodiments, the present disclosure provides compositions comprising one or more of such compounds, and / or pharmaceutically acceptable salts, hydrates, solvates, polymorphs, isomers, or combinations thereof. The present disclosure further provides pharmaceutical compositions comprising one or more compounds of the present disclosure together with a pharmaceutically acceptable carrier or excipient. In some embodiments, the present disclosure provides pharmaceutical compositions comprising a compound, a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combinations thereof, and at least one pharmaceutically acceptable excipient, carrier, adjuvant, or vehicle. In some embodiments, the present disclosure provides a therapeutically effective amount of such a compound, or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combinations thereof. In some embodiments, the present disclosure provides pharmaceutical compositions as described above, further comprising at least one second therapeutic agent. The present disclosure also provides pharmaceutical compositions comprising one or more compounds of the present disclosure (such as, pharmaceutically acceptable salts thereof) (i.e., as active agents, as therapeutic agents) and one or more pharmaceutically acceptable carriers or excipients. Pharmaceutical compositions contain one or more of such compounds (i.e., active agents), or a suitable fraction thereof, in a therapeutically effective amount. The compositions may optionally contain additional active agents. In some embodiments, the peptide products are at least about 90%, 95%, or 98% pure. Pharmaceutically acceptable excipients and carriers include pharmaceutically acceptable substances, materials, and vehicles. Non-limiting examples of types of excipients include liquid and solid fillers, diluents, binders, lubricants, glidants, surfactants, dispersing agents, disintegrants, emulsifiers, wetting agents, suspending agents, thickening agents, solvents, isotonicity agents, buffers, pH adjusters, absorption delaying agents, stabilizers, antioxidants, preservatives, antimicrobial agents, antibacterial agents, antifungal agents, chelating agents, adjuvants, sweeteners, flavoring agents, coloring agents, encapsulating materials, and coating materials. The use of such excipients in pharmaceutical formulations is well known in the art.Conventional vehicles and carriers include, but are not limited to, oils (e.g., vegetable oils such as olive oil and sesame oil), aqueous solvents (e.g., saline, buffered saline (e.g., phosphate-buffered saline [PBS]) and isotonic solutions (e.g., Ringer's solution)), and organic solvents (e.g., dimethyl sulfoxide and alcohols (e.g., ethanol, glycerol, and propylene glycol)). Except insofar as any conventional excipient or carrier is incompatible with the peptide product, the present disclosure encompasses the use of conventional excipients and carriers in formulations comprising the peptide product. See, for example, Remington: The Science and Practice of Pharmacy, 21st ed., Lippincott Williams and Wilkins, Philadelphia, Pennsylvania, USA (2005); Handbook of Pharmaceutical Excipients, 5th ed., Rowe et al., eds., The Pharmaceutical Press and the American Pharmaceutical Association (2005); Handbook of Pharmaceutical Additives, 3rd ed., Ash and Ash, eds., Gower Publishing Co. (2007); and Pharmaceutical Pre-Formulation and Formulation, Gibson, ed., CRC Press, Boca Raton, Florida (2004). The appropriateness of a particular formulation may depend on various factors, such as the chosen route of administration.Potential routes of administration of pharmaceutical compositions comprising compounds disclosed herein and the like can include, but are not limited to, oral, parenteral (including intradermal, subcutaneous, intramuscular, intravascular, intravenous, intraarterial, intraperitoneal, intracavity, and topical), topical (including transdermal), transmucosal, intranasal (e.g., via nasal spray or nasal drops), ophthalmic (e.g., via eye drops), pulmonary (e.g., via oral or nasal inhalation), buccal, sublingual, rectal (e.g., via suppository), vaginal (e.g., via suppository), and / or other suitable routes known to one of skill in the art.

[0037] In some embodiments, the compounds and compositions disclosed herein can be used as antagonists and / or modulators of orexin receptors and / or κ-opioid receptors (or kappa-opioid receptors, which in humans are G protein-coupled receptors encoded by the OPRK1 gene; abbreviated as KOR or KOP, and ketazocine is its ligand). In preferred embodiments, the compounds and / or compositions disclosed herein can be antagonists; i.e., antagonists of one or more orexin receptors (e.g., either OX1R or OX2R, or both OX1R and OX2R), and antagonists and / or modulators of KOR. The compounds and / or compositions disclosed herein can be selectively more antagonistic toward one or more orexin receptors compared to other orexin receptors (e.g., generally less antagonistic toward OX1R or OX2R compared to other orexin receptors). Thus, the compounds and / or compositions described above can be referred to herein as "orexin receptor antagonists." In some embodiments, the compounds may be antagonists and / or modulators of κ-opioid receptors. In some embodiments, the compounds and / or compositions of the present disclosure may be antagonists of one or more orexin receptors (i.e., orexin receptor antagonists), but are not antagonists of KOR. In some embodiments, for example, one or more compounds of the present disclosure and / or combinations thereof are preferably designed to have, and possess, the following properties when measured using standards in an in vitro cellular assay for effective therapeutic efficacy (e.g., the assays described in the Examples herein): (1)OX1R Kb < 100nM, OX2R Kb > 500nM, KOR Ki < 1000nM; (2) OX1R Kb < 100nM, OX2R Kb < 1000nM, KOR Ki < 1000nM; or (3) OX1R Kb < 100nM, OX2R Kb > 10000nM, KOR Ki < 1000; (4) OX1R Kb < 100nM, OX2R Kb < 1000nM, KOR Ki < 10000nM. In some embodiments, the present disclosure provides methods for preventing or treating conditions associated with orexin receptors and / or one or more κ-opioid receptors (i.e., methods of preventing or treating as orexin receptor antagonists). For in vivo assays, compounds and / or compositions of the present disclosure may be tested in animal models (such as rats) by measuring primary dependent measures (e.g., including but not limited to, time of first drug injection, total drug injection administered, drug intake rate, and total lever press failures), progression ratios (e.g., including but not limited to, time of first drug injection, breakpoint, final ratio at completion, and total lever presses and lever press failures), and state reinstatement (e.g., including but not limited to, time of first drug injection, and total lever presses and lever press failures). These tests and in vivo evaluations are designed, planned, and estimated using techniques known to those skilled in the art for the purpose of demonstrating the therapeutic utility and in vivo efficacy of the compounds (which are directed to reducing intake and reducing motivation for illicit drug abuse) (see, for example, Brain Research 1731 (2020), edited by James et al. (see, for example, Brodnik et al., editorial 145894); Gentile et al., Addict Biol 2018, 23(1):247-255; Brodnik et al., Behav Brain Res. 2015, September 15;291:377-384, doi:10.1016 / j.bbr.2015.05.051). Those skilled in the art will recognize that other suitable test methods exist.

[0038] In some embodiments, the present disclosure provides a method for preventing or treating a condition selected from the group consisting of central nervous system (CNS) disorders, substance addiction, dependence, panic, anxiety, depression, post-traumatic stress disorder (PTSD), neurodegeneration, autism, schizophrenia, and Alzheimer's disease (AD) in a subject in need thereof by administering to the subject one or more such compounds and / or a composition comprising one or more of such compounds, or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof. In some embodiments, the method can include administering a therapeutically effective amount of a composition comprising the compound, a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof. In some embodiments, the composition comprises a pharmaceutically acceptable salt or isotope of such a compound. In some embodiments, the composition can include an unlabeled form of the compound or an isotopically labeled form of the compound, wherein one or more atoms are replaced by an atom having a selected atomic mass or mass number. In some embodiments, the disclosure provides the use of a compound disclosed herein, a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof, in the preparation of a therapeutic medicament for preventing and / or treating a condition selected from the group consisting of central nervous system (CNS) disorder, substance addiction, dependence, panic, anxiety, depression, post-traumatic stress disorder (PTSD), neurodegeneration, autism, schizophrenia, and Alzheimer's disease (AD) in a subject in need thereof.Examples of substance addictions can include a person's addiction to one or more opioids (such as, but not limited to, heroin, morphine, oxycodone (e.g., OxyContin, Percocet), fentanyl and / or hydrocodone (e.g., Vicodin)), one or more stimulants (e.g., amphetamines (e.g., Adderall, Ritalin), cocaine, crack cocaine, methamphetamine), one or more sedatives and / or tranquilizers (e.g., but not limited to, benzodiazepines (e.g., Valium, Xanax, Klonopin) or barbiturates (e.g., Nembutal, Luminal, Phenobarbital)), or other addictive drugs as would be known to one of ordinary skill in the art. In some embodiments, the use can include a composition comprising a therapeutically effective amount of the compound, a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof. In some embodiments, such uses may include compositions of pharmaceutically acceptable salts or isotopes of the compounds. In some embodiments, such uses may include compositions comprising unlabeled or isotopically labeled forms of the compounds, where the compounds have the structure shown in the formula, where one or more atoms are replaced by atoms having selected atomic masses or mass numbers. The present disclosure also provides intermediates of the compounds disclosed herein, as well as methods for preparing the same. In some embodiments, such preparations may include using any of the intermediates disclosed herein. Other embodiments are also contemplated as would be understood by one skilled in the art.

[0039] The term "therapeutically effective amount" refers to an amount of compound that, when administered to a subject, is sufficient to prevent, reduce the risk of, delay the onset of, slow the progression of, or reverse the condition being treated, or to alleviate to some extent the condition or one or more symptoms or complications of the condition, in at least some of the subjects receiving the compound. The term "therapeutically effective amount" also refers to an amount of compound sufficient to elicit the biological or medical response in a cell, tissue, organ, or human that a physician or clinician seeks to achieve. The terms "treat," "treating," and "treatment" include alleviating, ameliorating, and preventing the progression of a condition, regressing or eliminating a condition or one or more symptoms or complications associated with the condition, and alleviating, ameliorating, or eradicating one or more causes of the condition. "Treatment" of a condition includes prevention of the condition. The terms "prevent," "preventing," and "prevention" include preventing, reducing the risk of, and delaying the onset of, a condition or one or more symptoms or complications associated with the condition. The term "medical conditions" (or, for short, "conditions") includes diseases and disorders. The terms "diseases" and "disorders" are used synonymously herein.

[0040] Throughout this specification, the expression "comprise" or variations thereof (such as "comprises" or "comprising") should be understood to include a specified integer (or component) or group of integers (or components), but not to exclude any other integer (or component) or group of integers (or components). The singular forms "a," "an," and "the" include the plural unless the context clearly indicates otherwise. The symbol "=" when used to refer to a chemical formula means "is." The term "including" can also mean "including but not limited to"; "including" and "including but not limited to" are used synonymously. The term "chemical substance" herein refers to a chemical compound (such as an organic compound or a mixture of compounds). "Chemical entity" includes, for example, chemical entities known in terms of structure, and if such chemical entities have orexin antagonist activity, they may be suitable as "therapeutic agents" in the methods and compositions disclosed herein. Additionally, those skilled in the art will recognize that the following abbreviations are commonly used: Me: Methyl Et: Ethyl t-Bu: tert-butyl Ar: aryl Ph: Phenyl BINAP: 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl Bn: Benzyl Ac: Acetyl Boc: tert-butyloxycarbonyl BSA: bovine serum albumin CbzCl: benzyl chloroformate CDI: carbonyldiimidazole DCM: dichloromethane DCE: dichloroethane DEAD: Diethyl azodicarboxylate DIPEA: N,N-diisopropylethylamine DMF: N,N-dimethylformamide DMSO: dimethyl sulfoxide CH2Cl2: dichloromethane EDC: N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide Et3N: Triethylamine EtOAc: ethyl acetate EtOH: Ethanol HCl: Hydrochloric acid HOAt: 1-hydroxy-7-aza-10-benzotriazole HOBT: Hydroxybenzotriazole hydrate LCMS: Liquid Chromatography Mass Spectrometry HPLC: High-performance liquid chromatography Hunig's base: N,N-diisopropylethylamine MeOH: Methanol MgSO4: Magnesium sulfate MTBE: Methyl tert-butyl ether NaHCO3: Sodium bicarbonate Na2CO3: Sodium carbonate K2CO3: Potassium carbonate NaOH: Sodium hydroxide NMM: N-methylmorpholine PtO2: platinum oxide Pd: Palladium Pd / C: Palladium / activated carbon PyClu: 1-(chloro-1-pyrrolidinylmethylene)pyrrolidinium hexafluorophosphate RT or rt: room temperature SOCl2: Thionyl chloride THF: tetrahydrofuran TFA: trifluoroacetic acid X-Phos: 2-(dicyclohexylphosphino)-2',4',6'-triisopropylbiphenyl HATU: 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate NMR: nuclear magnetic resonance ESI: electrospray ionization MS: mass spectrometry reaction

[0041] Thus, in some embodiments, the present disclosure provides a compound of the formula shown below: [ka] JPEG2025530768000035.jpg187158 or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof, compositions comprising same, methods of making same (e.g., as described in the Examples section), and methods of using same (e.g., for treating a condition); where the following chemical groups are present: R1 comprises an E that contains carbon (C) but no nitrogen (N), wherein E is linked to J or D by a double bond in formula I, or E is linked to A or D by a double bond in formula II; and R1 is H, alkyl, alkoxy, cycloalkyl, phenyl, aromatic or aryl, heteroaryl which is optionally a 5- or 6-membered heteroaryl, substituted aromatic or aryl, and substituted heteroaryl which is optionally a 5- or 6-membered heteroaryl. selected from the group consisting of: wherein when R1 is heteroaryl, R1 is optionally a 5- or 6-membered heteroaryl selected from the group consisting of pyrazolyl, triazolyl, oxazolyl, thiazolyl, thiophenyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl; wherein said aromatic, aryl or heteroaryl is unsubstituted, mono- or di-substituted; wherein the substituents are independently: (C 1~4 ) alkyl, (C 1~4 ) alkoxy, halogen, (C 1~3 ) fluoroalkyl, (C 1~3 ) fluoroalkoxy and (C 3~7 ) cycloalkyl; R2, R3, and R4 are independently H, alkyl, substituted alkyl, (C 1~4 ) alkyl, (C 1~4 ) alkoxy, (C 1~3 ) fluoroalkyl, (C 1~3 ) fluoroalkoxy, (C 3~7 ) cycloalkyl, and halogen (optionally F, Cl, or Br); wherein each of R2, R3, and R4 is independently and optionally substituted at each substitutable position with up to three independently selected substituents of one, two, or all of R2, R3, and R4; R5 is H, F, CH3, alkyl, substituted alkyl, (C 1~3 ) selected from the group consisting of fluoroalkyl, cycloalkyl, and R5 substituted at the carbon bearing Y, Z1, and Z2; wherein R5' is defined herein; R5' is selected from the group consisting of aromatic, aryl, heteroaryl, 5- or 6-membered heteroaryl, substituted aromatic or aryl, substituted heteroaryl or a fused two-heteroaryl ring system, optionally containing a 5- or 6-membered ring; wherein said aromatic, aryl or heteroaryl is unsubstituted, mono- or di- or tri-substituted; wherein the substituents are independently: (C 1~4 ) alkyl, (C 1~4 ) alkoxy, halogen, (C 1~3 ) fluoroalkyl, (C1~3 ) fluoroalkoxy, (C 3~7 ) cycloalkyl, and (C 3~7 ) heterocycloalkyl; R6 is H, F, CH3, alkyl, substituted alkyl, (C 1~3 ) fluoroalkyl, cycloalkyl, and R6 is selected from the group consisting of (C 1~3 ) R as alkyl to form a cyclic structure of alkyl bridge 10 or R 11 connected to either of the following; R7 is H, F, CH3, alkyl, substituted alkyl, (C 1~3 ) selected from the group consisting of fluoroalkyl, cycloalkyl, and R7 is substituted at the carbon bearing Y, Z1, and Z2, where R5' is defined herein; R8 is H, F, CH3, alkyl, substituted alkyl, (C 1~3 ) fluoroalkyl, cycloalkyl, and R8 is selected from the group consisting of (C 1~3 ) R as alkyl to form a cyclic structure of alkyl bridge 10 , R 11 or R 12 is connected to one of the following: R9 is H, F, CH3, alkyl, substituted alkyl, (C 1~3 ) fluoroalkyl, cycloalkyl, and R9 is selected from the group consisting of (C 1~3 ) R6 or R as alkyl forming the cyclic structure of the alkyl bridge 12 is connected to; R 10 is H, F, CH3, alkyl, substituted alkyl, (C 1~3 ) fluoroalkyl, cycloalkyl, and R 10 is (C 1~3 ) R6 or R as alkyl forming the cyclic structure of the alkyl bridge 11 is linked to; R 11 is H, F, CH3, alkyl, substituted alkyl, (C 1~3) fluoroalkyl, cycloalkyl, and R 11 is (C 1~3 ) linked to R6 as an alkyl forming a cyclic structure of alkyl bridge; R 12 is H, F, CH3, alkyl, substituted alkyl, (C 1~3 ) fluoroalkyl, cycloalkyl, and R 12 is (C 1~3 ) linked to R9 as an alkyl forming a cyclic structure of the alkyl bridge; X is optionally absent to provide a 5-membered pyrrolidine ring; CH, O, and CR a R b where R a and R b is selected from the group consisting of alkyl, cycloalkyl, and fluoroalkyl; and here: the carbon atom at position 2 of said piperidine or pyrrolidine is optionally in the absolute (S) configuration; or the carbon atom at position 2 of the morpholine ring (where X is oxygen) is optionally in the absolute (R) configuration; Y is absent for the purpose of providing R5' directly linked to the carbon bearing the Z1 and Z2 groups; O; NH; CH2OR5'; CH2; NR a selected from the group consisting of: where R a is selected from the group consisting of alkyl, cycloalkyl, and heteroalkyl; The 5- or 6-membered heteroaryl is selected from the group consisting of pyrrolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, and oxadiazolyl; and Z1 and Z2 are independently H, F, (C 1~4 ) alkyl, (C 1~3 ) fluoroalkyl, (C 1~3 ) fluoroalkoxy, and (C 2~7 ) cycloalkyl; and here: The fused or non-fused ring system ABJDE is a 5-membered heteroaryl, optionally imidazole (where A and J are nitrogen while B, E, D are carbon); pyrazole (where A and B are nitrogen while D, E, and J are carbon); optionally fused to one or more further ring systems or non-fused; The fused ring system BJMGKL is an arrangement of the variables outlined above to provide the group consisting of 6-membered aromatic, 6-membered aryl, 6-membered substituted aromatic, 6-membered substituted aryl, 6-membered substituted heteroaryl, 6-membered unsubstituted heteroaryl, 5- or 6-membered cycloalkyl, and 5- or 6-membered heterocycloalkyl; and where optionally: A is nitrogen, optionally imidazole or pyrazole; B is carbon or nitrogen; J is carbon or nitrogen; D is carbon; E is carbon, where R1 is a group as defined above; M is selected from the group consisting of carbon, CH, CHR, CHR, CR, CR, CR, CR, O, and N; G is selected from the group consisting of carbon, CH, CHR, CHR, CR, CR, CR, CR, and O; K is selected from the group consisting of carbon, CH, CHR, CHR, CR, R, CR, CR, CR, and O; and L is selected from the group consisting of carbon, CH, CHR2, CHR3, CR2R3, CR2, CR3, CR4, O, and N.

[0042] In a preferred embodiment, the intermediates, reaction conditions, etc. used in preparing the compounds are described in detail in the Examples section, and therefore will not be described in detail here, but those skilled in the art will understand from the above description that the same content is reproduced in the description of this preferred aspect (i.e., incorporated herein). The present disclosure also provides a method for preparing a pharmaceutical composition, comprising combining at least one compound of the present disclosure with at least one pharmaceutically acceptable excipient. Methods for preparing such combinations (i.e., combinations of at least one compound, etc., and at least one pharmaceutical composition) are well known in the art, and therefore will not be described in detail for this aspect, but are incorporated herein.

[0043] Thus, the present disclosure provides, in preferred embodiments, a compound of any of Examples 1-263 (see Tables 1 and 3), and / or combinations thereof, and / or pharmaceutically acceptable salts, hydrates, solvates, polymorphs, isomers, or combinations thereof. In some preferred embodiments, the compound is selected from the group consisting of the compounds of Examples 4, 6, 7, 8, 10, 12, 13, 20, 22, 24, 25-29, 34, 40, 42-50, 53-64, 66-69, 73, 75, 78, 80, 89, 90, 92, 94, 95, 97, 107, 111, 112, 117-119, 122-142, 147-151, 156, 158, 171-183, 185-198, 201-203, 205, 207, 208, 210-214, 223, and 224; and / or combinations thereof, and / or pharmaceutically acceptable salts, hydrates, solvates, polymorphs, isomers, or combinations thereof. In a most preferred embodiment, the present disclosure provides a compound selected from the group consisting of the compounds of Examples 53, 55, 66, 95, 112, 118, 119, 122, 123, 124, 129, 130, 131, 134, 135, 138, 139, 140, 141, 142, 147, 148, 156, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 191, 195, 203, 205, 211, 223, and 224; and / or combinations thereof, and / or pharmaceutically acceptable salts, hydrates, solvates, polymorphs, isomers, or combinations thereof. In some embodiments, the compound is unlabeled or isotopically labeled. In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound disclosed herein, and / or a combination thereof, and / or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof; and at least one pharmaceutically acceptable carrier, adjuvant, and / or vehicle. In a preferred embodiment, the pharmaceutical composition comprises a therapeutically effective amount of the compound, its pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, and / or combination thereof.In some embodiments, the composition further comprises at least one second therapeutic agent. In some preferred embodiments, the present disclosure provides a method for antagonizing and / or modulating at least one orexin receptor and / or at least one kappa-opioid receptor in a cell, the method comprising exposing the cell to a compound and / or composition of the present disclosure, which may optionally be an in vitro method. In some preferred embodiments, the method for modulating at least one orexin receptor and / or at least one kappa-opioid receptor in a subject in need thereof comprises administering to the subject a compound and / or composition of the present disclosure. In some preferred embodiments, the method for treating a condition selected from the group consisting of substance addiction, substance dependence, panic, anxiety, depression, post-traumatic stress disorder (PTSD), neurodegeneration, autism, schizophrenia, pain, Alzheimer's disease (AD), and a central nervous system (CNS) disorder in a subject in need thereof comprises administering to the subject a compound and / or composition of the present disclosure.

[0044] In some preferred embodiments, the substance that corresponds to the substance addiction or substance dependence is: one or more opioids (optionally heroin, morphine, oxycodone, fentanyl, and hydrocodone); optionally, one or more stimulants selected from the group consisting of amphetamine, cocaine, crack cocaine, and methamphetamine; one or more sedatives and / or tranquilizers, benzodiazepines, and barbiturates, is selected from the group consisting of:

[0045] In some embodiments, the compound antagonizes at least one orexin receptor and / or antagonizes or modulates at least one kappa-opioid receptor. In some preferred embodiments, the present disclosure provides methods for making any preceding claimed compound or composition using at least one available combination of acid intermediates, amine intermediates, and methods shown in Table 2.

[0046] All references cited in this disclosure are incorporated herein by reference in their entirety. Specific embodiments are further described in the following examples. These embodiments are provided by way of illustration only and are not intended to limit the scope of the claims in any way.

[0047] Example In accordance with the present disclosure, the following intermediates were prepared and used in the synthesis of exemplary compounds claimed herein: 1. Prepared Carboxylic Acid Group-Containing Intermediate - Carboxylic Acid Group [ka]

[0048] 2. Prepared Secondary Amine-Containing Intermediates – Amine Group [ka] JPEG2025530768000038.jpg116158

[0049] I. General Synthetic Methods and Procedures General method All temperatures are in °C. Commercially available starting materials were used as received without further purification. Unless otherwise specified, all reactions were carried out in oven-dried glassware under a nitrogen atmosphere. Compounds were purified by flash column chromatography on silica gel or preparative HPLC. The compounds described in this disclosure were characterized by LC-MS data (retention time t R are expressed in min; molecular weights obtained by mass spectrometry are expressed in g / mol).

[0050] LC-MS under acidic conditions Method A: Agilent 1100 Series with mass spectrometry detection (MS: Agilent single quadrupole). Column: Zorbax SB (3.5 μm, 4.6 x 150 mm). Conditions: MeCN (0.1% FA) [Gradient eluent A]; water (0.1% FA) [Gradient eluent B]. Gradient: 95% B + 5% B for 5 min (flow rate: 0.8 ml / min). Detection: UV 280 / 254 nm + MS.

[0051] Method B: Agilent 1100 Series with mass spectrometry detection (MS: Agilent single quadrupole). Column: X-Bridge C18 (3.5 μm, 4.6 x 150 mm). Conditions: MeCN (0.1% FA) [Gradient eluent A]; water (0.1% FA) [Gradient eluent B]. Gradient: 95% B + 5% B for 5 min (Flow rate: 0.8 ml / min). Detection: UV 280 / 254 nm + MS.

[0052] In general, the compounds of the present disclosure can be prepared by methods known to those skilled in the art and modern techniques in the art. The following schemes 1 to 4 show synthetic routes for the compounds of the present disclosure. Other equivalent schemes that would be readily apparent to a synthetic organic chemist or medicinal chemist can also be used alternatively to synthesize various portions of the molecules as shown in the general schemes described herein.

[0053] Synthesis of Carboxylic Acid-Containing Intermediates - Carboxylic Acid Group [ka] Step 1: Synthesis of HBS-037-036: Ethyl-3-phenyl-1H-pyrazole-5-carboxylate (0.5 g, 2.31 mmol) was dissolved in acetone (10.0 mL). K2CO3 (0.96 g, 6.9 mmol) was added, followed by 1-bromo-2-chloroethane (0.1 mL, 11.6 mmol). The rxn mixture was heated at 55 °C for 16 hours. LCMS data indicated the formation of the desired product (m / z value, 279.0) and a small amount of by-product. The rxn mixture was filtered, and the solid was washed with ethyl acetate. The filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography (mobile phase: EtOAc:hexane gradient). 0.6 g of liquid product was isolated (93.2% yield). C 14 H 15 Calculated MS(ESI) mass for ClN2O2 is 278.7; [M+H] + The m / z value of was 279.0. Step 2: Synthesis of HBS-037-040: Compound HBS-037-036 (0.55 g, 1.97 mmol) was dissolved in dry THF (6.0 mL). DIBAL (12.0 mL, 1.0 M solution, 11.8 mmol) was added in an ice-cooled bath. The rxn mixture was stirred and gradually warmed to room temperature over 16 hours. LCMS data indicated the formation of the desired product (m / z value, 237.0). The rxn mixture was quenched with 1.0 N aqueous NaOH and diluted with ethyl acetate (10.0 mL). The rxn mixture was filtered through a celite bed and washed with ethyl acetate (10.0 mL x 3). The EtOAc layer was separated and washed with water, then brine. The organic layer was dried over anhydrous sodium sulfate. Evaporation of the solvent afforded 0.4 g of crude product (85.6% yield). 12 H 13 Calculated MS(ESI) mass for ClNO is 236.7; [M+H] + The m / z value of was 237.0. Step 3: Synthesis of HBS-037-042: Compound HBS-037-040 (0.47 g, 1.97 mmol) was dissolved in dry DMF (12.0 mL). NaH (0.12 g, 2.96 mmol) was added under ice cooling. The rxn mixture was stirred and gradually warmed to room temperature over 16 hours. LCMS data showed the formation of the desired product (m / z value, 201.1). The rxn mixture was diluted with water, and the product was extracted with ethyl acetate. The combined ethyl acetate layers were separated and dried over anhydrous sodium sulfate. The crude product was obtained by evaporating the solvent. The crude product was purified by column chromatography (mobile phase: EtOAc:hexane gradient). 0.26 g of solid product was obtained (yield 65.3%). C 12 H 12 Calculated MS(ESI) mass for NO is 200.2; [M+H] + The m / z value of was 201.1. Step 4: Synthesis of HBS-037-043: Compound HBS-037-042 (0.25 g, 1.25 mmol) was dissolved in DCM (5.0 mL). NBS (0.24 g, 1.37 mmol) was added, and the resulting mixture was stirred at room temperature for 16 hours. LCMS data indicated the formation of the desired product (m / z value, 280.9). The solvent was evaporated to give the crude product. The crude product was purified by column chromatography (mobile phase: EtOAc:hexane gradient). 0.29 g of liquid product was obtained (yield 81.7%). 12 H 11 Calculated MS(ESI) mass for BrNO is 279.1; [M+H] + The m / z value of was 280.9. Step 5: Synthesis of HBS-037-054: Compound HBS-037-043 (0.025 g, 0.09 mmol) was dissolved in anhydrous THF (1.0 mL) under a nitrogen atmosphere. The reaction mixture was cooled to -78.0 °C, and n-BuLi (0.12 mL, 1.6 M) was added to the rxn mixture. The rxn mixture was stirred at -78.0 °C for 30 minutes. Dry carbon dioxide gas was bubbled through the rxn mixture at -65 °C, and the rxn mixture was allowed to warm gradually to room temperature. LCMS data indicated the formation of the desired product (m / z 245), a debrominated by-product (m / z 201), and some unknown product. The rxn mixture was quenched with water and extracted with ethyl acetate. The ethyl acetate layer was separated to recover the debrominated product. The aqueous layer was acidified with 1 M HCl solution and evaporated to dryness to give 0.022 g of solid product. 13 H 12 Calculated MS(ESI) mass for N2O3 is 244.3; [M+H] + The m / z value of was 245.0; 1 H NMR (400 MHz, chloroform-d) δ ppm 4.06 - 4.15 (m, 2 H), 4.16 - 4.25 (m, 2 H), 5.03 - 5.10 (s, 2 H), 7.32 - 7.40 (m, 3 H), 7.60 - 7.69 (m, 2 H). [ka] Step 1: Synthesis of HBS-037-191: Ethyl benzoylacetate (0.5 g, 2.6 mmol) was dissolved in DMSO (5.0 mL). NBS (0.51 g, 2.86 mmol) was added, and the rxn mixture was stirred at ambient temperature for 24 hours. LCMS showed product formation (m / z value, 270.9). The rxn mixture was diluted with water, and the product was extracted with ethyl acetate. The ethyl acetate layer was separated and dried over anhydrous Na2SO4. The crude product was obtained by evaporating the solvent. The crude product was purified using a combi-flash system (mobile phase: EtOAc:hexane gradient). 0.42 g of product was obtained (yield 59.7%). C 11 H 11 Calculated MS(ESI) mass for BrO3 is 271.1; [M+H]+ The m / z value of was 270.9. Step 2: Synthesis of HBS-037-192: Compound HBS-037-191 (0.42 g, 1.55 mmol) was dissolved in anhydrous acetonitrile (5.0 mL). 2-Aminopyridine (0.15 g, 1.55 mmol) was added, and the rxn mixture was stirred at 80° C. for 1 hour. LCMS showed product formation (m / z value, 267.1). The rxn mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified using a combi-flash system (mobile phase: EtOAc:hexane gradient). 0.24 g of product was obtained (yield 58.0%). C 16 H 14 Calculated MS(ESI) mass for N2O2 is 266.3; [M+H] + The m / z of was 267.1. Step 3: Synthesis of HBS-037-193: Compound HBS-037-192 (0.24 g, 0.9 mmol) was dissolved in MeOH (5.0 mL). 1.0 N aqueous NaOH solution (4.51 mL, 4.51 mmol) was added, and the rxn mixture was stirred at 60 °C for 3 hours. LCMS showed product formation (m / z value, 239). The rxn mixture was concentrated under reduced pressure. The solid was dissolved in water and acidified with 2.0 M aqueous HCl (pH = 5). The precipitate was filtered and washed with water (10.0 mL x 3) to give 0.2 g of solid product. C 14 H 10 Calculated MS(ESI) mass for N2O2 is 238.2; [M+H] + The m / z value of was 239.1; 1 H NMR (400 MHz, chloroform-d) δ ppm 7.04 (t, J = 6.93 Hz, 1 H) 7.33 - 7.48 (m, 4 H) 7.70 - 7.78 (m, 3 H) 9.41 (d, J = 7.04 Hz, 1 H). [ka] Step 1: Synthesis of HBS-037-163: 2-Phenylpyrazolo[1,5-a]pyridine-3-carboxylic acid ethyl ester (0.2 g, 0.75 mmol) was dissolved in MeOH (6.0 mL). 1.0 N aqueous NaOH solution (3.8 mL, 3.8 mmol) was added, and the rxn mixture was stirred at 60 °C for 24 hours. LCMS showed product formation (m / z value, 239.1). The rxn mixture was concentrated under reduced pressure. The solid was dissolved in water and acidified with 1.0 M aqueous HCl (pH = 5). The precipitate was filtered and washed with water (10.0 mL x 3) to give 0.18 g of solid product. C 14 H 10 Calculated MS(ESI) mass for N2O2 is 238.2; [M+H] + The m / z value of was 239.1; 1 H NMR (400 MHz, chloroform-d) δ ppm 6.90–7.03 (m, 1 H), 7.27–7.47 (m, 4 H), 7.75–7.78 (ddd, J = 4.86, 3.21, 1.54 Hz, 2 H), 8.18–8.28 (dd, J = 8.99, 0.70 Hz, 1 H), 8.49–8.56 (dd, J = 6.90, 0.73 Hz, 1 H). [ka] Step 1: Synthesis of HBS-039-013: Pyrazolo[1,5-a]pyridine-2-carboxylic acid (1.0 g, 6.17 mmol) was dissolved in ethanol (20.0 mL). A catalytic amount of concentrated sulfuric acid (0.5 mL) was added, and the rxn mixture was refluxed for 16 hours. LCMS data showed the formation of the product (m / z value, 191.1). The rxn mixture was concentrated under reduced pressure and neutralized with saturated aqueous sodium bicarbonate. The product was extracted with ethyl acetate. The ethyl acetate layer was separated and dried over anhydrous Na2SO4. The product was obtained by evaporating the solvent. (Yield) 1.2 g of product was obtained. C 10 H 10 Calculated MS(ESI) mass for N2O2 is 190.2; [M+H] + The m / z value of was 191.1. Step 2: Synthesis of HBS-039-014: HBS-039-013 (1.17 g, 6.17 mmol) was dissolved in DCM (25.0 mL). NBS (1.1 g, 6.17 mmol) was added, and the rxn mixture was stirred at ambient temperature for 16 hours. LCMS data indicated product formation (m / z value, 271.0). The rxn mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified using an ISCO combi-flash chromatography system (mobile phase: EtOAc:hexane gradient). 1.5 g of product was obtained (yield 90.4%). C 10 Calculated MS(ESI) mass for H9BrN2O2 is 269.1; [M+H] + The m / z value of was 271.0. Step 3: Synthesis of HBS-039-015: HBS-039-014 (0.2 g, 0.74 mmol) was dissolved in a mixture of dioxane / water (8.0:2.0 v / v mL). Phenylboronic acid (0.11 g, 0.89 mmol) and K2CO3 (0.3 g, 2.23 mmol) were added, followed by Pd(dppf)Cl2·DCM2 (0.06 g, 0.07 mmol). The rxn mixture was stirred under a nitrogen atmosphere at 80 °C for 5 h. LCMS data indicated product formation (m / z value, 267). The rxn mixture was filtered through a Celite bed and washed with ethyl acetate. The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified using an ISCO combi-flash chromatography system (mobile phase: EtOAc:hexane gradient). Yield: 0.2 g of product. C 16 H 14 Calculated MS(ESI) mass for N2O2 is 266.3; [M+H] + The m / z value of was 267.1. Step 4: Synthesis of HBS-039-018: HBS-039-015 (0.2 g, 0.74 mmol) was dissolved in MeOH (6.0 mL). 1.0 N aqueous NaOH solution (3.7 mL, 3.7 mmol) was added, and the rxn mixture was stirred at 60 °C for 16 hours. LCMS data indicated product formation (m / z value, 239.1). The rxn mixture was concentrated under reduced pressure and diluted with water. The aqueous layer was acidified with 1.0 M aqueous HCl solution (pH = 5). The precipitate was filtered and washed with water (5.0 mL x 3) to obtain 0.16 g of solid product (92.6% yield). C 14 H 10 Calculated MS(ESI) mass for N2O2 is 238.2; [M+H] + The m / z value of was 239.1. [ka] Step 1: Synthesis of HBS-039-016: Imidazo[1,2-a]pyridine-2-carboxylic acid (1.0 g, 5.26 mmol) was dissolved in DCM (20.0 mL). NBS (1.0 g, 5.78 mmol) was added, and the rxn mixture was stirred at ambient temperature for 16 hours. LCMS data indicated product formation (m / z value, 271.0). The rxn mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified using an ISCO combi-flash chromatography system (mobile phase: EtOAc:hexane gradient). 1.4 g of product was obtained (98.9% yield). C 10 Calculated MS(ESI) mass for H9BrN2O2 is 269.1; [M+H] + The m / z value of was 271.0. Step 2: Synthesis of HBS-039-017: Compound HBS-039-016 (0.2 g, 0.74 mmol) was dissolved in a mixture of dioxane / water (8.0:2.0 v / v mL). Phenylboronic acid (0.11 g, 0.89 mmol) and K2CO3 (0.3 g, 2.23 mmol) were added, followed by Pd(dppf)Cl2·DCM2 (0.06 g, 0.07 mmol). Under a nitrogen atmosphere, the rxn mixture was stirred at 80 °C for 5 hours. LCMS data indicated product formation (m / z value, 267.1). The rxn mixture was filtered through a Celite bed and washed with ethyl acetate. The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified using an ISCO combi-flash chromatography system (mobile phase: EtOAc:hexane gradient). Yield: 0.2 g of product. C 16 H 14 Calculated MS(ESI) mass for N2O2 is 266.3; [M+H] + The m / z value of was 267.1. Step 3: Synthesis of HBS-039-019: Compound HBS-039-017 (0.2 g, 0.74 mmol) was dissolved in MeOH (6.0 mL). 1.0 N aqueous NaOH solution (3.7 mL, 3.7 mmol) was added, and the rxn mixture was stirred at 60 °C for 16 hours. LCMS data indicated product formation (m / z value, 239.1). The rxn mixture was concentrated under reduced pressure and diluted with water. The aqueous layer was acidified with 1.0 M HCl solution (pH = 5). The precipitate was filtered and washed with water (5.0 mL x 3) to give 0.11 g of solid product (62.1% yield). C 14 H 10 Calculated MS(ESI) mass for N2O2 is 238.2; [M+H] + The m / z value of was 239.1. [ka] Step 1: Synthesis of HBS-039-130: Ethyl benzoylacetate (3.0 g, 15.61 mmol) was dissolved in DCM (20.0 mL). NBS (3.1 g, 17.17 mmol) was added, and the rxn mixture was stirred at 35° C. for 48 hours. LCMS showed product formation (m / z value, 272.0). The rxn mixture was diluted with water, and the product was extracted with ethyl acetate. The ethyl acetate layer was separated and dried over anhydrous Na2SO4. The crude product was obtained by evaporating the solvent. The crude product was purified using a combi-flash system (mobile phase: EtOAc:hexane gradient). 3.75 g of product was obtained (yield 88.6%). C 11 H 11 Calculated MS(ESI) mass for BrO3 is 271.1; [M+H] + The m / z value of was 272.0. Step 2: Synthesis of HBS-039-135: Compound HBS-039-130 (0.25 g, 0.92 mmol) was dissolved in anhydrous acetonitrile (5.0 mL). Pyrazin-2-amine (0.088 g, 0.92 mmol) was added, and the rxn mixture was stirred at 80 °C for 24 hours. LCMS showed product formation (m / z value, 268.1). The rxn mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified using a combi-flash system (mobile phase: EtOAc:hexane gradient). 0.13 g of product was obtained (yield 51.5%). C 15 H 13 Calculated MS(ESI) mass for N3O2 is 267.28; [M+H] + The m / z value of was 268.1. Step 3: Synthesis of HBS-039-139: Compound HBS-039-135 (0.12 g, 0.45 mmol) was dissolved in MeOH (2.5 mL). 1.0 N aqueous NaOH solution (2.24 mL, 2.24 mmol) was added, and the rxn mixture was stirred at 60° C. for 3 hours. LCMS showed product formation (m / z value, 240.0). The rxn mixture was concentrated under reduced pressure. The solid was dissolved in water and acidified with 2.0 M aqueous HCl (pH=5). The precipitate was filtered and washed with water (1.0 mL×3), yielding 0.11 g of solid product. 13Calculated MS(ESI) mass for H9N3O2 is 239.23; [M+H] + The m / z value of was 240.0. [ka] Step 1: Synthesis of HBS-039-147: 1-Ethynyl-4-fluorobenzene (0.5 g, 4.16 mmol) was dissolved in anhydrous THF (5.0 mL). n-BuLi (5.2 mL, 8.32 mmol) was added at -78 °C, and the rxn mixture was stirred at -78 °C for 1 hour. Ethyl chloroformate (1.59 mL, 16.7 mmol) was added at -78 °C, and the rxn mixture was gradually warmed to ambient temperature. LCMS data showed product formation (m / z value, 193.0). The rxn mixture was diluted with aqueous NH4Cl, and the product was extracted with ethyl acetate. The combined ethyl acetate layers were separated and dried over anhydrous sodium sulfate. The crude product was obtained by evaporating the solvent. (Yield) 0.8 g of crude product was obtained. C 11 Calculated MS(ESI) mass for H9FO2 is 192.19; [M+H] + The m / z value of was 193.0. Step 2: Synthesis of HBS-039-148: Compound HBS-039-147 (0.4 g, 2.08 mmol) and 1-aminopyridinium iodide (0.46 g, 2.08 mmol) were dissolved in anhydrous DMF (5.0 mL). Anhydrous K2CO3 (0.72 g, 5.2 mmol) was added, and the reaction mixture was stirred at ambient temperature for 16 hours. LCMS data showed product formation (m / z value, 285.1). The reaction mixture was diluted with water, and the precipitate was filtered. The crude product was obtained by drying the precipitate. The crude product was purified using a combi-flash system (mobile phase: EtOAc:hexane gradient). 0.4 g of product was obtained (yield 67.6%). C 16 H 13 Calculated MS(ESI) mass for FN2O2 is 284.29; [M+H] + The m / z value of was 285.1. Step 3: Synthesis of HBS-039-150: Compound HBS-039-148 (0.4 g, 1.41 mmol) was dissolved in MeOH (7.0 mL). 1.0 N aqueous NaOH solution (7.0 mL, 7.0 mmol) was added, and the reaction mixture was refluxed for 8 hours. LCMS showed the product formation (m / z value, 257.0). The reaction mixture was concentrated under reduced pressure. The solid was dissolved in water and acidified with 2.0 M aqueous HCl (pH = 5). The precipitate was filtered and washed with water (5.0 mL x 3) to give 0.35 g of solid product (97.5% yield). 14 Calculated MS(ESI) mass for H9FN2O2 is 256.23; [M+H] + The m / z value of was 257.0. [ka] Step 1: Synthesis of HBS-039-188: 1-Ethynyl-2-fluorobenzene (1.0 g, 8.33 mmol) was dissolved in anhydrous THF (10.0 mL). n-BuLi (10.4 mL, 16.65 mmol) was added at -78 °C, and the rxn mixture was stirred at -78 °C for 1 hour. Ethyl chloroformate (3.8 mL, 40.0 mmol) was added at -78 °C, and the rxn mixture was gradually warmed to ambient temperature. LCMS data showed product formation (m / z value, 193.0). The rxn mixture was diluted with aqueous NH4Cl, and the product was extracted with ethyl acetate. The combined ethyl acetate layers were separated and dried over anhydrous sodium sulfate. The crude product was obtained by evaporating the solvent. (Yield) 1.6 g of crude product was obtained. C 11 Calculated MS(ESI) mass for H9FO2 is 192.19; [M+H] + The m / z value of was 193.0. Step 2: Synthesis of HBS-039-189: Compound HBS-039-188 (1.6 g, 8.33 mmol) and 1-aminopyridinium iodide (1.85 g, 8.33 mmol) were dissolved in anhydrous DMF (15.0 mL). Anhydrous K2CO3 (2.88 g, 20.81 mmol) was added, and the reaction mixture was stirred at ambient temperature for 16 hours. LCMS data indicated product formation (m / z value, 285.1). The reaction mixture was diluted with water, and the product was extracted with ethyl acetate. The combined ethyl acetate layers were separated and dried over anhydrous sodium sulfate. The crude product was obtained by evaporating the solvent. The crude product was purified by column chromatography (mobile phase: EtOAc:hexane gradient). 1.56 g of product was obtained (66.0% yield). C 16 H 13 Calculated MS(ESI) mass for FN2O2 is 284.29; [M+H] + The m / z value of was 285.1. Step 3: Synthesis of HBS-039-192: Compound HBS-039-189 (1.56 g, 5.5 mmol) was dissolved in MeOH (10.0 mL). 1.0 N aqueous NaOH solution (16.5 mL, 16.5 mmol) was added, and the reaction mixture was refluxed for 12 hours. LCMS showed product formation (m / z value, 257.0). The reaction mixture was concentrated under reduced pressure. The solid was dissolved in water and acidified with 2.0 M aqueous HCl (pH = 5). The precipitate was filtered and washed with water (5.0 mL x 3) to give 1.3 g of solid product (yield 92.3%). 14 Calculated MS(ESI) mass for H9FN2O2 is 256.23; [M+H] + The m / z value of was 257.0. [ka] Step 1: Synthesis of HBS-054-005: Ethyl benzoylacetate (2.13 g, 11.1 mmol) was dissolved in DCM (20.0 mL). NBS (1.8 g, 11.1 mmol) and TsOH·H2O (0.38 g, 2.0 mmol) were added, and the reaction mixture was stirred at ambient temperature for 24 hours. LCMS showed product formation (m / z value, 272.0). The reaction mixture was diluted with water, and the product was extracted with ethyl acetate. The ethyl acetate layer was separated and dried over anhydrous Na2SO4. The crude product was obtained by evaporating the solvent. The crude product was purified using a combi-flash system (mobile phase: EtOAc:hexane gradient). 2.1 g of product was obtained (70.0% yield). C 11 H 11 Calculated MS(ESI) mass for BrO3 is 271.1; [M+H] + The m / z value of was 272.0. Step 2: Synthesis of HBS-054-010: Compound HBS-054-005 (1.5 g, 5.56 mmol) was dissolved in anhydrous acetonitrile (20.0 mL). 2-Amino-5-fluoropyridine (1.9 g, 16.67 mmol) was added, and the reaction mixture was stirred at 80° C. for 16 hours. LCMS showed the product formation (m / z value, 285.0). The reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified using a combi-flash system (mobile phase: EtOAc:hexane gradient). 1.2 g of product was obtained (75.0% yield). 16 H 13 Calculated MS(ESI) mass for FN2O2 is 284.29; [M+H] + The m / z value of was 285.0. Step 3: Synthesis of HBS-054-014: Compound HBS-054-010 (1.2 g, 4.22 mmol) was dissolved in MeOH (12.0 mL). 1.0 N aqueous NaOH solution (8.44 mL, 8.5 mmol) was added, and the reaction mixture was stirred at 60° C. for 12 hours. LCMS showed product formation (m / z value, 257.0). The reaction mixture was concentrated under reduced pressure. The solid was dissolved in water and acidified with 2.0 M aqueous HCl (pH=5). The precipitate was filtered and washed with water (5.0 mL×3) to give 0.92 g of solid product (84.0% yield). 14Calculated MS(ESI) mass for H9FN2O2 is 256.23; [M+H] + The m / z value of was 257.0. [ka] Step 1: Synthesis of HBS-054-011: Ethyl 3-(4-fluorophenyl)-3-oxopropanoate (1.5 g, 7.14 mmol) was dissolved in anhydrous acetonitrile (20.0 mL). 2-Aminopyridine (2.0 g, 21.4 mmol) was added, followed by CBr4 (4.7 g, 14.27 mmol), and the reaction mixture was stirred at 80 °C for 16 hours. LCMS showed product formation (m / z value, 285.0). The reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified using a combi-flash system (mobile phase: EtOAc:hexane gradient). 1.9 g of product was obtained (yield: 95.0%). 16 H 13 Calculated MS(ESI) mass for FN2O2 is 284.29; [M+H] + The m / z value of was 285.0. Step 2: Synthesis of HBS-054-015: Compound HBS-054-011 (1.5 g, 5.28 mmol) was dissolved in MeOH (15.0 mL). 1.0 N aqueous NaOH solution (10.6 mL, 10.56 mmol) was added, and the reaction mixture was stirred at 60° C. for 12 hours. LCMS showed product formation (m / z value, 257.0). The reaction mixture was concentrated under reduced pressure. The solid was dissolved in water and acidified with 2.0 M aqueous HCl (pH=5). The precipitate was filtered and washed with water (5.0 mL×3) to give 1.07 g of solid product (79.0% yield). 14 Calculated MS(ESI) mass for H9FN2O2 is 256.23; [M+H] + The m / z value of was 257.0. [ka] Step 1: Synthesis of HBS-054-012: Ethyl 3-(2-fluorophenyl)-3-oxopropanoate (1.5 g, 7.14 mmol) was dissolved in anhydrous acetonitrile (20.0 mL). 2-Aminopyridine (2.0 g, 21.4 mmol) was added, followed by CBr4 (4.7 g, 14.27 mmol), and the reaction mixture was stirred at 80 °C for 4 hours. LCMS showed product formation (m / z value, 285.0). The reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified using a combi-flash system (mobile phase: EtOAc:hexane gradient). 1.83 g of product was obtained (yield: 90.0%). 16 H 13 Calculated MS(ESI) mass for FN2O2 is 284.29; [M+H] + The m / z value of was 285.0. Step 2: Synthesis of HBS-054-016: Compound HBS-054-012 (1.5 g, 5.28 mmol) was dissolved in MeOH (15.0 mL). 1.0 N aqueous NaOH solution (10.6 mL, 10.56 mmol) was added, and the reaction mixture was stirred at 60° C. for 12 hours. LCMS showed product formation (m / z value, 257.0). The reaction mixture was concentrated under reduced pressure. The solid was dissolved in water and acidified with 2.0 M aqueous HCl (pH=5). The precipitate was filtered and washed with water (5.0 mL×3), yielding 1.1 g of solid product (81.0% yield). 14 Calculated MS(ESI) mass for H9FN2O2 is 256.23; [M+H] + The m / z value of was 257.0. [ka] Step 1: Synthesis of HBS-054-020: Ethyl benzoylacetate (1.5 g, 7.81 mmol) was dissolved in anhydrous acetonitrile (20.0 mL). 2-Amino-4-fluoropyridine (2.6 g, 23.4 mmol) was added, followed by CBr4 (5.2 g, 15.6 mmol), and the reaction mixture was stirred at 80 °C for 16 hours. LCMS showed the product formation (m / z value, 285.0). The reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified using a combi-flash system (mobile phase: EtOAc:hexane gradient). 0.9 g of product was obtained (41.0% yield). 16 H 13 Calculated MS(ESI) mass for FN2O2 is 284.29; [M+H] + The m / z value of was 285.0. Step 2: Synthesis of HBS-054-021: Compound HBS-054-020 (0.9 g, 3.17 mmol) was dissolved in MeOH (10.0 mL). 1.0 N aqueous NaOH solution (6.3 mL, 6.34 mmol) was added, and the reaction mixture was stirred at 60° C. for 12 hours. LCMS showed product formation (m / z value, 257.0). The reaction mixture was concentrated under reduced pressure. The solid was dissolved in water and acidified with 2.0 M aqueous HCl solution (pH=5). The precipitate was filtered and washed with water (5.0 mL×3) to give 0.37 g of solid product (41.0% yield). 14 Calculated MS(ESI) mass for H9FN2O2 is 256.23; [M+H] + The m / z value of was 257.0. [ka] Step 1: Synthesis of HBS-054-028: Ethyl imidazo[1,2-a]pyridine-2-carboxylate (3.6 g, 18.94 mmol) was dissolved in DCM (80.0 mL). NBS (3.4 g, 18.94 mmol) was added, and the rxn mixture was stirred at ambient temperature for 16 hours. LCMS data indicated product formation (m / z value, 270.0). The rxn mixture was concentrated under reduced pressure to give the crude product. This crude product was purified using an ISCO combi-flash chromatography system (mobile phase: EtOAc:hexane gradient). Yield: 5.1 g of product. C 10 Calculated MS(ESI) mass for H9BrN2O2 is 269.1; [M+H] + The m / z value of was 270.0. Step 2: Synthesis of HBS-054-035: Compound HBS-054-028 (1.5 g, 5.6 mmol) and 4-fluorophenylboronic acid (1.2 g, 8.4 mmol) were dissolved in a mixture of dioxane / water (24.0:6.0 v / v mL). Anhydrous CsCO (3.8 g, 11.75 mmol) was added, followed by Pd(dba) (0.26 g, 0.28 mmol) and X-Phos (0.4 g, 0.84 mmol). The rxn mixture was stirred at 80 °C for 12 h under a nitrogen atmosphere. LCMS data indicated product formation (m / z value, 285.0). The rxn mixture was filtered through a Celite bed and washed with ethyl acetate. The filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified using an ISCO combi-flash chromatography system (mobile phase: EtOAc:hexane gradient). 1.4 g of product was obtained (yield 85.0%). 16 H 13 Calculated MS(ESI) mass for FN2O2 is 284.29; [M+H] + The m / z value of was 285.0. Step 3: Synthesis of HBS-054-039: Compound HBS-054-035 (1.4 g, 4.93 mmol) was dissolved in MeOH (15.0 mL). 1.0 N aqueous NaOH (10.0 mL, 9.86 mmol) was added, and the rxn mixture was refluxed for 12 hours. LCMS data indicated product formation (m / z value, 257.0). The rxn mixture was concentrated under reduced pressure and diluted with water. The aqueous layer was acidified with 2.0 M aqueous HCl (pH = 5). The precipitate was filtered and washed with water (5.0 mL x 3) to give 0.56 g of solid product (45.0% yield). C 14 Calculated MS(ESI) mass for H9FN2O2 is 256.23; [M+H] + The m / z value of was 257.0. [ka] Step 1: Synthesis of HBS-054-028: Ethyl imidazo[1,2-a]pyridine-2-carboxylate (3.6 g, 18.94 mmol) was dissolved in DCM (80.0 mL). NBS (3.4 g, 18.94 mmol) was added, and the rxn mixture was stirred at ambient temperature for 16 hours. LCMS data indicated product formation (m / z value, 270.0). The rxn mixture was concentrated under reduced pressure to give the crude product. This crude product was purified using an ISCO combi-flash chromatography system (mobile phase: EtOAc:hexane gradient). Yield: 5.1 g of product. C 10 Calculated MS(ESI) mass for H9BrN2O2 is 269.1; [M+H] + The m / z value of was 270.0. Step 2: Synthesis of HBS-054-036: Compound HBS-054-028 (1.5 g, 5.6 mmol) and 2-fluorophenylboronic acid (1.2 g, 8.4 mmol) were dissolved in a mixture of dioxane / water (24.0:6.0 v / v mL). Anhydrous CsCO (3.8 g, 11.75 mmol) was added, followed by Pd(dba) (0.26 g, 0.28 mmol) and X-Phos (0.4 g, 0.84 mmol). The rxn mixture was stirred at 80 °C under a nitrogen atmosphere for 12 hours. LCMS data indicated product formation (m / z value, 285.0). The rxn mixture was filtered through a Celite bed and washed with ethyl acetate. The filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified using an ISCO combi-flash chromatography system (mobile phase: EtOAc:hexane gradient). 1.2 g of product was obtained (yield 75.0%). 16 H 13 Calculated MS(ESI) mass for FN2O2 is 284.29; [M+H] + The m / z value of was 285.0. Step 3: Synthesis of HBS-054-040: Compound HBS-054-036 (1.2 g, 4.22 mmol) was dissolved in MeOH (15.0 mL). 1.0 N aqueous NaOH (8.4 mL, 8.44 mmol) was added, and the rxn mixture was refluxed for 12 hours. LCMS data indicated product formation (m / z value, 257.0). The rxn mixture was concentrated under reduced pressure and diluted with water. The aqueous layer was acidified with 2.0 M aqueous HCl (pH = 5). The precipitate was filtered and washed with water (5.0 mL x 3) to give 0.7 g of solid product (65.0% yield). C 14 Calculated MS(ESI) mass for H9FN2O2 is 256.23; [M+H] + The m / z value of was 257.0. [ka] Step 1: Synthesis of HBS-054-033: Pyrazolo[1,5-a]pyridine-2-carboxylic acid methyl ester (2.4 g, 13.6 mmol) was dissolved in DCM (54.0 mL). NBS (2.5 g, 14.3 mmol) was added, and the rxn mixture was stirred at ambient temperature for 16 h. LCMS data indicated product formation (m / z value, 256.0). The rxn mixture was concentrated under reduced pressure to give the crude product. The crude product was purified using an ISCO combi-flash chromatography system (mobile phase: EtOAc:hexane gradient). Yield: 3.5 g of product. MS (ESI) mass calculated for C9H7BrN2O2 was 255.07; [M+H] + The m / z value of was 256.0. Step 2: Synthesis of HBS-054-037: Compound HBS-054-033 (1.5 g, 5.9 mmol) and 4-fluorophenylboronic acid (1.2 g, 8.86 mmol) were dissolved in a mixture of dioxane / water (24.0:6.0 v / v mL). Anhydrous CsCO (4.0 g, 12.39 mmol) was added, followed by Pd(dba) (0.27 g, 0.29 mmol) and X-Phos (0.4 g, 0.88 mmol). The rxn mixture was stirred at 80 °C under a nitrogen atmosphere for 12 hours. LCMS data indicated product formation (m / z value, 271.0). The rxn mixture was filtered through a celite bed and washed with ethyl acetate. The filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified using an ISCO combi-flash chromatography system (mobile phase: EtOAc:hexane gradient). 1.24 g of product was obtained (78.0% yield). 15 H 11 Calculated MS(ESI) mass for FN2O2 is 270.26; [M+H] + The m / z value of was 271.0. Step 3: Synthesis of HBS-054-041: Compound HBS-054-037 (1.2 g, 4.59 mmol) was dissolved in MeOH (15.0 mL). 1.0 N aqueous NaOH solution (9.2 mL, 9.18 mmol) was added, and the rxn mixture was refluxed for 12 hours. LCMS data indicated product formation (m / z value, 257.0). The rxn mixture was concentrated under reduced pressure and diluted manually. The aqueous layer was acidified with 2.0 M aqueous HCl (pH = 5). The precipitate was filtered and washed with water (5.0 mL x 3) to give 1.0 g of solid product (85.0% yield). C 14 Calculated MS(ESI) mass for H9FN2O2 is 256.23; [M+H] + The m / z value of was 257.0. [ka] Step 1: Synthesis of HBS-054-033: Pyrazolo[1,5-a]pyridine-2-carboxylic acid methyl ester (2.4 g, 13.6 mmol) was dissolved in DCM (54.0 mL). NBS (2.5 g, 14.3 mmol) was added, and the rxn mixture was stirred at ambient temperature for 16 h. LCMS data indicated product formation (m / z value, 256.0). The rxn mixture was concentrated under reduced pressure to give the crude product. This crude product was purified using an ISCO combi-flash chromatography system (mobile phase: EtOAc:hexane gradient). Yield: 3.5 g of product. MS (ESI) mass calculated for C9H7BrN2O2 was 255.07; [M+H] + The m / z value of was 256.0. Step 2: Synthesis of HBS-054-038: Compound HBS-054-033 (1.5 g, 5.9 mmol) and 2-fluorophenylboronic acid (1.2 g, 8.86 mmol) were dissolved in a mixture of dioxane / water (24.0:6.0 v / v mL). Anhydrous CsCO (4.0 g, 12.39 mmol) was added, followed by Pd(dba) (0.27 g, 0.29 mmol) and X-Phos (0.4 g, 0.88 mmol). The rxn mixture was stirred at 80 °C under a nitrogen atmosphere for 12 hours. LCMS data indicated product formation (m / z value, 271.0). The rxn mixture was filtered through a celite bed and washed with ethyl acetate. The filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified using an ISCO combi-flash chromatography system (mobile phase: EtOAc:hexane gradient). 1.4 g of product was obtained (yield 86.0%). 15 H 11 Calculated MS(ESI) mass for FN2O2 is 270.26; [M+H] + The m / z value of was 271.0. Step 3: Synthesis of HBS-054-042: Compound HBS-054-038 (1.4 g, 5.18 mmol) was dissolved in MeOH (15.0 mL). 1.0 N aqueous NaOH (10.4 mL, 10.36 mmol) was added, and the rxn mixture was refluxed for 12 hours. LCMS data indicated product formation (m / z value, 257.0). The rxn mixture was concentrated under reduced pressure and diluted with water. The aqueous layer was acidified with 2.0 M aqueous HCl (pH = 5). The precipitate was filtered and washed with water (5.0 mL x 3) to give 1.0 g of solid product (85.0% yield). C 14 Calculated MS(ESI) mass for H9FN2O2 is 256.23; [M+H] + The m / z value of was 257.0. [ka] Step 1: Synthesis of HBS-054-076: Ethyl benzoylacetate (1.5 g, 7.81 mmol) was dissolved in anhydrous acetonitrile (20.0 mL). 2-Amino-4-(trifluoromethyl)pyridine (3.8 g, 23.4 mmol) was added, followed by CBr4 (5.2 g, 15.6 mmol), and the reaction mixture was stirred at 80 °C for 16 h. LCMS showed product formation (m / z value, 335.0). The reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified using a combi-flash system (mobile phase: EtOAc:hexane gradient). 1.0 g of product was obtained (38.0% yield). 17 H 13 Calculated MS(ESI) mass for F3N2O2 is 334.29; [M+H] + The m / z value of was 335.0. Step 2: Synthesis of HBS-054-080: Compound HBS-054-076 (1.0 g, 2.99 mmol) was dissolved in MeOH (10.0 mL). 1.0 N aqueous NaOH solution (6.0 mL, 6.0 mmol) was added, and the reaction mixture was refluxed for 12 hours. LCMS showed product formation (m / z value, 307.0). The reaction mixture was concentrated under reduced pressure. The solid was dissolved in water and acidified with 2.0 M aqueous HCl (pH = 5). The precipitate was filtered and washed with water (5.0 mL x 3) to give 0.3 g of solid product (33.0% yield). 15 Calculated MS(ESI) mass for H9F3N2O2 is 306.24; [M+H] + The m / z value of was 307.0. [ka] Step 1: Synthesis of HBS-054-061: Methyl 4-(4-fluorophenyl)-2,4-dioxobutanoate (2.2 g, 10.68 mmol) was dissolved in anhydrous THF (40.0 mL). Hydrazine monohydrate (0.56 g, 11.21 mmol) was added. The reaction mixture was heated at reflux for 3 hours. LCMS data indicated the formation of the desired product (m / z value, 221.0). The reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (mobile phase: EtOAc:hexane gradient). 1.2 g of product was isolated (yield 51.0%). 11 Calculated MS(ESI) mass for H9FN2O2 is 220.2; [M+H] + The m / z value of was 221.0. Step 2: Synthesis of HBS-054-062: Compound HBS-054-061 (0.64 g, 2.91 mmol) was dissolved in acetone (15.0 mL). K2CO3 (0.8 g, 5.82 mmol) was added, followed by 1-bromo-2-chloroethane (0.5 g, 3.49 mmol). The reaction mixture was heated at 55 °C for 16 hours. LCMS data showed the formation of the desired product (m / z value, 283.0) and a small amount of by-product. The reaction mixture was filtered, and the solid was washed with ethyl acetate. The filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography (mobile phase: EtOAc:hexane gradient). 0.7 g of product was isolated (85.0% yield). C 13 H 12 Calculated MS(ESI) mass for ClFN2O2 is 282.7; [M+H] + The m / z value of was 283.0. Step 3: Synthesis of HBS-054-064: Compound HBS-054-062 (0.7 g, 2.48 mmol) was dissolved in dry THF (10.0 mL). 2.0 M LAH in THF (1.24 mL, 2.48 mmol) was added in an ice-cooled bath. The reaction mixture was gradually warmed to room temperature and stirred for 16 hours. LCMS data indicated the formation of the desired product (m / z value, 255.0). The reaction mixture was quenched with 1.0 N aqueous NaOH solution and diluted with ethyl acetate (10.0 mL). The reaction mixture was filtered through a celite bed and washed with ethyl acetate (10.0 mL x 3). The organic layer was separated and washed with water, then brine. The organic layer was dried over anhydrous sodium sulfate. Evaporation of the solvent afforded 0.6 g of crude product (95.0% yield). C 12 H 12 Calculated MS(ESI) mass for ClFNO is 254.69; [M+H] + The m / z value of was 255.0. Step 4: Synthesis of HBS-054-065: Compound HBS-054-064 (0.6 g, 2.36 mmol) was dissolved in dry DMF (5.0 mL). NaH (0.11 g, 4.72 mmol) was added under ice cooling. The reaction mixture was gradually warmed to room temperature and stirred for 16 hours. LCMS data showed the formation of the desired product (m / z value, 219.0). The reaction mixture was diluted with water, and the product was extracted with ethyl acetate. The combined ethyl acetate layers were separated and dried over anhydrous sodium sulfate. The crude product was obtained by evaporating the solvent. The crude product was purified by column chromatography (mobile phase: EtOAc:hexane gradient). 0.46 g of solid product was obtained (yield 88.0%). C 12 H 11 Calculated MS(ESI) mass for FNO is 218.23; [M+H] + The m / z value of was 219.0. Step 5: Synthesis of HBS-054-071: Compound HBS-054-065 (0.46 g, 2.11 mmol) was dissolved in DCM (7.0 mL). NBS (0.41 g, 2.32 mmol) was added, and the reaction mixture was stirred at room temperature for 16 hours. LCMS data showed the formation of the desired product (m / z value, 298.0). The crude product was obtained by evaporating the solvent. The crude product was purified by column chromatography (mobile phase: EtOAc:hexane gradient). 0.25 g of product was obtained (40.0% yield). C 12 H 10 Calculated MS(ESI) mass for BrFNO is 297.12; [M+H] + The m / z value of was 298.0. Step 6: Synthesis of HBS-054-088: Compound HBS-054-071 (1.15 g, 3.85 mmol) was dissolved in anhydrous THF (20 mL) under a nitrogen atmosphere. The reaction mixture was cooled to -78.0 °C, and 1.6 M n-BuLi in hexane (4.81 mL, 7.7 mmol) was added to the reaction mixture. The reaction mixture was stirred at -78.0 °C for 30 minutes. Dry carbon dioxide gas was bubbled through the reaction mixture at -65 °C, and the reaction mixture was gradually warmed to room temperature. LCMS data indicated the formation of the desired product (m / z value, 263.0), a debrominated by-product, and some unknown product. The reaction mixture was quenched with water and extracted with ethyl acetate. The ethyl acetate layer was separated, and the debrominated product was collected. The aqueous layer was acidified with 2 M aqueous HCl, resulting in a precipitate. The precipitate was filtered and dried to give 0.6 g of solid product (yield 60.0%). 13 H 11 Calculated MS(ESI) mass for FN2O3 is 262.24; [M+H] + The m / z value of was 263.0. [ka] Step 1: Synthesis of HBS-039-198: To a solution of NaOMe (1.25 g of Na in 25.0 mL of methanol) was added 2-fluoroacetophenone (5.0 g, 36.19 mmol) dropwise. The mixture was stirred at ambient temperature for 30 minutes. A solution of diethyl oxalate (5.81 g, 39.81 mmol) in anhydrous methanol (25.0 mL) was added, and the reaction mixture was stirred at ambient temperature for 16 hours. LCMS data indicated the formation of the desired product (m / z value, 225.0). The reaction mixture was concentrated under reduced pressure to obtain the crude product. This crude product was dissolved in cold water and acidified with 2.0 M aqueous HCl. The precipitate was filtered and dried to give 8.62 g of crude product. 11 Calculated MS(ESI) mass for H9FO4 is 224.19; [M+H] + The m / z value of was 225.0. Step 2: Synthesis of HBS-039-200: Compound HBS-039-198 (8.62 g, 36.19 mmol) was dissolved in IPA (100.0 mL). Hydrazine monohydrate (2.1 mL, 43.4 mmol) was added, and the reaction mixture was heated at reflux for 3 hours. LCMS data showed the formation of the desired product (m / z value, 221.0) and a hydrolysis by-product (m / z value, 207.0). The reaction mixture was cooled to ambient temperature, and a precipitate was obtained. The precipitate was filtered to give 7.19 g of crude product (90.2% yield). C 11 Calculated MS(ESI) mass for H9FN2O2 is 220.2; [M+H] + The m / z value of C was 221.0. 10 The calculated mass for H7FN2O2 is 206.17; [M+H] + The m / z value of was 207.0. Step 3: Synthesis of HBS-055-002: The crude product of compound HBS-039-200 (7.19 g, 32.65 mmol) was dissolved in anhydrous methanol (100.0 mL). Concentrated sulfuric acid (4.0 mL) was added, and the reaction mixture was heated at reflux for 24 hours. LCMS data indicated the formation of the desired product (m / z value, 221.0). The reaction mixture was cooled to ambient temperature and neutralized with saturated aqueous sodium bicarbonate to obtain a precipitate. The precipitate was filtered and dried to give 7.19 g of solid product (yield). C 11Calculated MS(ESI) mass for H9FN2O2 is 220.2; [M+H] + The m / z value of was 221.0. Step 4: Synthesis of HBS-055-004: Compound HBS-055-002 (7.19 g, 32.65 mmol) was dissolved in acetone (100.0 mL). K2CO3 (13.53 g, 97.95 mmol) was added, followed by 1-bromo-2-chloroethane (13.5 mL, 163.3 mmol). The reaction mixture was heated at 65 °C for 24 hours. LCMS data indicated the formation of the desired product (m / z value, 283.0). The reaction mixture was filtered, and the solid was washed with ethyl acetate. The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (mobile phase: EtOAc:hexane gradient). 2.85 g of product was isolated (30.9% yield). C 13 H 12 Calculated MS(ESI) mass for ClFN2O2 is 282.7; [M+H] + The m / z value of was 283.0. Step 5: Synthesis of HBS-055-007: Compound HBS-055-004 (2.85 g, 10.1 mmol) was dissolved in dry THF (25.0 mL). The reaction mixture was cooled to 0° C. in an ice bath. A 1.0 M solution of DIBAL in hexane (25.2 mL, 25.2 mmol) was added. The reaction mixture was gradually warmed to room temperature and stirred for 16 hours. LCMS data indicated the formation of the desired product (m / z value, 255.1). The reaction mixture was quenched with aqueous NH4Cl and diluted with ethyl acetate (100.0 mL). The reaction mixture was filtered through a celite bed and washed with ethyl acetate. The organic layer was separated and washed with brine. The organic layer was dried over anhydrous sodium sulfate. Evaporation of the solvent gave 2.57 g of crude product (yield). C 12 H 12 Calculated MS(ESI) mass for ClFNO is 254.69; [M+H] + The m / z value of was 255.0. Step 6: Synthesis of HBS-055-008: Compound HBS-055-007 (2.57 g, 10.1 mmol) was dissolved in dry DMF (20.0 mL). Under ice cooling, 60.0% NaH (0.81 g, 20.2 mmol) in mineral oil was added. The reaction mixture was gradually warmed to room temperature and stirred for 16 hours. LCMS data showed the formation of the desired product (m / z value, 219.1). The reaction mixture was diluted with water, and the product was extracted with ethyl acetate. The combined ethyl acetate layers were separated and dried over anhydrous sodium sulfate. The crude product was obtained by evaporating the solvent. The crude product was purified by column chromatography (mobile phase: EtOAc:hexane gradient). 1.17 g of solid product was obtained (yield: 53.2%). C 12 H 11 Calculated MS(ESI) mass for FNO is 218.23; [M+H] + The m / z value of was 219.1. Step 7: Synthesis of HBS-055-010: Compound HBS-055-008 (1.17 g, 5.36 mmol) was dissolved in DCM (15.0 mL). NBS (1.05 g, 5.9 mmol) was added, and the reaction mixture was stirred at ambient temperature for 16 hours. LCMS data showed the formation of the desired product (m / z value, 299.0). The crude product was obtained by evaporating the solvent. The crude product was purified by column chromatography (mobile phase: EtOAc:hexane gradient). 1.27 g of product was obtained (79.7% yield). C 12 H 10 Calculated MS(ESI) mass for BrFNO is 297.12; [M+H] + The m / z value of was 299.0. Step 8: Synthesis of HBS-055-013: Compound HBS-055-010 (1.27 g, 4.27 mmol) was dissolved in anhydrous THF (15.0 mL) under a nitrogen atmosphere. The reaction mixture was cooled to −78.0° C. 1.6 M n-BuLi in hexane (5.33 mL, 8.54 mmol) was added, and the reaction mixture was stirred at −78.0° C. for 30 minutes. Dry carbon dioxide gas was bubbled through the reaction mixture at −65° C., and the reaction mixture was gradually warmed to room temperature. LCMS data indicated the formation of the desired product (m / z value, 263.1), a debrominated by-product, and some unknown product. The reaction mixture was quenched with water and extracted with ethyl acetate. The ethyl acetate layer was separated, and the debrominated product was collected. The aqueous layer was acidified with 2 M aqueous HCl, resulting in a precipitate. The precipitate was filtered and dried to give 0.84 g of solid product (75.0% yield). 13 H 11 Calculated MS(ESI) mass for FN2O3 is 262.24; [M+H] + The m / z value of was 263.1. [ka] Step 1: Synthesis of HBS-055-191: Ethyl 5-hydroxy-1H-pyrazole-3-carboxylate (1.0 g, 6.40 mmol) was dissolved in anhydrous acetonitrile (15.0 mL). Anhydrous K2CO3 (3.54 g, 25.62 mmol) was added, and the reaction mixture was stirred at ambient temperature for 15 minutes. 1,3-Dibromopropane (0.72 mL, 7.05 mmol) was added, and the reaction mixture was heated at reflux for 6 hours. LCMS data indicated product formation (m / z value, 197.1). The reaction mixture was cooled to ambient temperature and filtered. The filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified using an ISCO combi-flash chromatography system (mobile phase: EtOAc:hexane gradient). 1.03 g of product was obtained (81.97% yield). CH 12 Calculated MS(ESI) mass for N2O3 is 196.20; [M+H] + The m / z value of was 197.1. Step 2: Synthesis of HBS-055-192: Compound HBS-055-191 (1.03 g, 5.25 mmol) was dissolved in DCM (15.0 mL). NBS (0.93 g, 5.25 mmol) was added, and the mixture was stirred at ambient temperature for 16 hours. LCMS data indicated product formation (m / z value, 275.0). The reaction mixture was diluted with water, and the product was extracted with DCM. The combined DCM layers were separated and dried over anhydrous sodium sulfate. The crude product was obtained by evaporating the solvent. The crude product was purified using an ISCO combi-flash system (mobile phase: EtOAc:hexane gradient). (Yield) 1.44 g of product was obtained. CH 11 Calculated MS(ESI) mass for BrN2O3 is 275.1; [M+H] + The m / z value of was 275.0. Step 3: Synthesis of HBS-055-194: Compound HBS-055-192 (0.4 g, 1.45 mmol) and phenylboronic acid (0.27 g, 2.18 mmol) were dissolved in a mixture of dioxane / water (9:1 v / v mL). Anhydrous K2CO3 (0.6 g, 4.36 mmol) was added, followed by Pd(dppf)Cl2·DCM2 (0.06 g, 0.073 mmol). The rxn mixture was stirred at 100 °C under a nitrogen atmosphere for 6 hours. LCMS data indicated product formation (m / z value, 273.1). The rxn mixture was filtered through a Celite bed and washed with ethyl acetate. The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified using an ISCO combi-flash chromatography system (mobile phase: EtOAc:hexane gradient). 0.37 g of product was obtained (94.7% yield). C 15 H 16 Calculated MS(ESI) mass for N2O3 is 272.3; [M+H] + The m / z value of was 273.1. Step 4: Synthesis of HBS-055-197: Compound HBS-055-194 (0.37 g, 1.38 mmol) was dissolved in MeOH (5.0 mL). 1.0 N aqueous NaOH (4.1 mL, 4.1 mmol) was added, and the rxn mixture was refluxed for 6 hours. LCMS data indicated product formation (m / z value, 245.1). The rxn mixture was concentrated under reduced pressure and diluted with water. The aqueous layer was acidified with 2.0 M aqueous HCl (pH = 5). The precipitate was filtered and washed with water (2.0 mL x 3) to give 0.26 g of solid product (77.3% yield). C 13 H 12 Calculated MS(ESI) mass for N2O3 is 244.25; [M+H] + The m / z value of was 245.1. [ka] Step 1: Synthesis of HBS-062-005: Morpholine-3-carboxylic acid (1.0 g, 7.63 mmol) was dissolved in water (6.0 mL). Anhydrous NaNO2 (0.79 g, 11.44 mmol) was added, and the mixture was cooled to 0 °C in an ice bath. 12.0 M aqueous HCl (1.27 mL, 15.26 mmol) was added, and the reaction mixture was allowed to warm slowly to ambient temperature for 16 h. LCMS data indicated product formation (m / z value, 161.1). The reaction mixture was extracted with ethyl acetate. The combined ethyl acetate layers were separated and dried over anhydrous sodium sulfate. The crude product was obtained by evaporation of the solvent. (Yield) 1.22 g of product. MS (ESI) mass calculated for C5H8N2O4 was 160.13; [M+H] + The m / z value of was 161.1. Step 2: Synthesis of HBS-062-007: Compound HBS-062-005 (1.22 g, 7.63 mmol) was dissolved in anhydrous toluene (10.0 mL). The rxn mixture was cooled to 0° C. in an ice bath. Anhydrous TFA (1.6 mL, 11.44 mmol) was added, and the reaction mixture was allowed to warm gradually to ambient temperature for 16 hours. LCMS data indicated product formation (m / z value, 143.1). The reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified using an ISCO combi-flash chromatography system (mobile phase: EtOAc:hexane gradient). 1.02 g of product was obtained (94.1% yield). MS (ESI) mass calculated for C5H6N2O3 was 142.11; [M+H] + The m / z value of was 143.1. Step 3: Synthesis of HBS-062-009: Compound HBS-062-007 (1.0 g, 7.18 mmol) was dissolved in xylene (10.0 mL). Ethyl propiolate (0.95 mL, 9.33 mmol) was added, and the reaction mixture was heated at 120° C. for 6 hours. LCMS data indicated product formation (m / z value, 197.1). The reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified using an ISCO combi-flash chromatography system (mobile phase: EtOAc:hexane gradient). 1.0 g of product was obtained (71.0% yield). CH 12 Calculated MS(ESI) mass for N2O3 is 196.20; [M+H] + The m / z value of was 197.1. Step 4: Synthesis of HBS-062-010: Compound HBS-062-009 (1.0 g, 5.1 mmol) was dissolved in DCM (15.0 mL). NBS (1.0 g, 5.61 mmol) was added, and the mixture was stirred at ambient temperature for 16 hours. LCMS data showed product formation (m / z value, 275.0). The reaction mixture was diluted with water, and the product was extracted with DCM. The combined DCM layers were separated and dried over anhydrous sodium sulfate. The crude product was obtained by evaporating the solvent. The crude product was purified using an ISCO combi-flash system (mobile phase: EtOAc:hexane gradient). 1.4 g of product was obtained (99.7% yield). CH 11Calculated MS(ESI) mass for BrN2O3 is 275.1; [M+H] + The m / z value of was 275.0. Step 5: Synthesis of HBS-052-011: Compound HBS-062-010 (0.4 g, 1.45 mmol) and phenylboronic acid (0.27 g, 2.18 mmol) were dissolved in a mixture of dioxane / water (9:1 v / v mL). Anhydrous K2CO3 (0.6 g, 4.36 mmol) was added, followed by Pd(dppf)Cl2·DCM2 (0.06 g, 0.073 mmol). The rxn mixture was stirred at 100 °C under a nitrogen atmosphere for 6 hours. LCMS data indicated product formation (m / z value, 273.1). The rxn mixture was filtered through a Celite bed and washed with ethyl acetate. The filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified using an ISCO combi-flash chromatography system (mobile phase: EtOAc:hexane gradient). 0.39 g of product was obtained (95.5% yield). C 15 H 16 Calculated MS(ESI) mass for N2O3 is 272.3; [M+H] + The m / z value of was 273.1. Step 6: Synthesis of HBS-062-013: Compound HBS-062-011 (0.39 g, 1.43 mmol) was dissolved in MeOH (8.0 mL). 1.0 N aqueous NaOH (4.3 mL, 4.3 mmol) was added, and the rxn mixture was refluxed for 6 hours. LCMS data indicated product formation (m / z value, 245.1). The rxn mixture was concentrated under reduced pressure and diluted with water. The aqueous layer was acidified with 2.0 M aqueous HCl (pH = 5). The precipitate was filtered and washed with water (2.0 mL x 3) to give 0.23 g of solid product (65.8% yield). C 13 H 12 Calculated MS(ESI) mass for N2O3 is 244.25; [M+H] + The m / z value of was 245.1. [ka] Step 1: Synthesis of HBS-062-019: Ethyl 5-amino-1H-pyrazole-4-carboxylate (1.0 g, 6.44 mmol) was dissolved in DCM (15.0 mL). The reaction mixture was cooled to 0 °C in an ice bath. NBS (1.38 g, 7.73 mmol) was added, and the mixture was stirred at ambient temperature for 16 h. LCMS data indicated product formation (m / z value, 236.0). The reaction mixture was diluted with saturated aqueous NaHCO3. The product was extracted with DCM. The combined DCM layers were separated and dried over anhydrous sodium sulfate. The crude product was obtained by evaporating the solvent. The crude product was purified using an ISCO combi-flash system (mobile phase: DCM:methanol gradient). 0.62 g of product was obtained (41.1% yield). Calculated MS(ESI) mass for C6H8BrN3O2 is 234.05; [M+H] + The m / z value of was 236.0. Step 2: Synthesis of HBS-062-021: Compound HBS-062-019 (0.62 g, 2.65 mmol) and 1,1,3,3-tetraethoxypropane (0.76 mL, 3.18 mmol) were dissolved in acetic anhydride (10.0 mL). The reaction mixture was heated at 70 °C for 24 hours. LCMS data indicated product formation (m / z value, 272.0). The reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude product was diluted with water and neutralized with saturated aqueous NaHCO3. The precipitate was filtered and dried to give 0.3 g of product (41.9% yield). MS (ESI) mass calculated for C9H8BrN3O2 was 270.08; [M+H] + The m / z value of was 272.0. Step 3: Synthesis of HBS-062-024: Compound HBS-062-021 (0.3 g, 1.11 mmol) and phenylboronic acid (0.2 g, 1.67 mmol) were dissolved in a mixture of dioxane / water (7:1 v / v mL). Anhydrous K2CO3 (0.46 g, 3.33 mmol) was added, followed by Pd(dppf)Cl2·DCM2 (0.045 g, 0.056 mmol). The rxn mixture was stirred at 100 °C under a nitrogen atmosphere for 4 hours. LCMS data indicated product formation (m / z value, 268.1). The rxn mixture was filtered through a Celite bed and washed with ethyl acetate. The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified using an ISCO combi-flash chromatography system (mobile phase: EtOAc:hexane gradient). 0.25 g of product was obtained (84.2% yield). C 15 H 13 Calculated MS(ESI) mass for N3O2 is 267.28; [M+H] + The m / z value of was 268.1. Step 4: Synthesis of HBS-062-027: Compound HBS-062-024 (0.25 g, 0.94 mmol) was dissolved in MeOH (6.0 mL). 1.0 N aqueous NaOH (1.9 mL, 1.87 mmol) was added, and the rxn mixture was refluxed for 8 hours. LCMS data indicated product formation (m / z value, 240.1). The rxn mixture was concentrated under reduced pressure and diluted with water. The aqueous layer was acidified with 2.0 M aqueous HCl (pH = 5). The precipitate was filtered and washed with water (2.0 mL x 3) to give 0.11 g of solid product (49.2% yield). C 13 Calculated MS(ESI) mass for H9N3O2 is 239.23; [M+H] + The m / z value of was 240.1. [ka] Step 1: Synthesis of HBS-062-020: 1-Ethynylpyrimidine (1.0 g, 9.61 mmol) was dissolved in anhydrous THF (12.0 mL). n-BuLi (7.2 mL, 11.53 mmol) was added at -78 °C, and the rxn mixture was stirred at -78 °C for 30 minutes. Ethyl chloroformate (1.4 mL, 14.41 mmol) was added at -78 °C, and the rxn mixture was gradually warmed to ambient temperature for 3 hours. LCMS data indicated product formation (m / z value, 177.1). The rxn mixture was diluted with aqueous NH4Cl, and the product was extracted with ethyl acetate. The combined ethyl acetate layers were separated and dried over anhydrous sodium sulfate. The crude product was obtained by evaporating the solvent. The crude product was purified using an ISCO combi-flash system (mobile phase: DCM:MeOH gradient). 0.78 g of product was obtained (46.1% yield). Calculated MS(ESI) mass for C9H8N2O2 is 176.17; [M+H] + The m / z value of was 177.1. Step 2: Synthesis of HBS-062-023: Compound HBS-062-020 (0.75 g, 4.25 mmol) and 1-aminopyridinium iodide (1.13 g, 5.11 mmol) were dissolved in anhydrous DMF (10.0 mL). Anhydrous K2CO3 (1.47 g, 10.63 mmol) was added, and the reaction mixture was stirred at ambient temperature for 16 hours. LCMS data indicated product formation (m / z value, 269.1). The rxn mixture was diluted with water, and the product was extracted with ethyl acetate. The combined ethyl acetate layers were separated and dried over anhydrous sodium sulfate. The crude product was obtained by evaporating the solvent. The crude product was purified using an ISCO combi-flash system (mobile phase: ethyl acetate:hexane gradient). 0.48 g of product was obtained (42.1% yield). C 14 H 12 Calculated MS(ESI) mass for N4O2 is 268.27; [M+H] + The m / z value of was 269.1. Step 3: Synthesis of HBS-062-028: Compound HBS-062-023 (0.28 g, 1.04 mmol) was dissolved in MeOH (8.0 mL). 1.0 N aqueous NaOH solution (2.1 mL, 2.09 mmol) was added, and the reaction mixture was refluxed for 6 hours. LCMS showed product formation (m / z value, 241.1). The reaction mixture was concentrated under reduced pressure. The solid was dissolved in water and acidified with 2.0 M aqueous HCl (pH = 5). The precipitate was filtered and washed with water (2.0 mL x 3) to give 0.22 g of solid product (87.5% yield). 12 Calculated MS(ESI) mass for H8N4O2 is 240.22; [M+H] + The m / z value of was 241.1. [ka] Step 1: Synthesis of HBS-062-022: 1-Ethynylpyridine (2.0 g, 19.4 mmol) was dissolved in anhydrous THF (15.0 mL). n-BuLi (14.6 mL, 23.3 mmol) was added at -78 °C, and the rxn mixture was stirred at -78 °C for 30 minutes. Ethyl chloroformate (2.2 mL, 23.3 mmol) was added at -78 °C, and the rxn mixture was gradually warmed to ambient temperature for 3 hours. LCMS data indicated product formation (m / z value, 176.1). The rxn mixture was diluted with aqueous NH4Cl, and the product was extracted with ethyl acetate. The combined ethyl acetate layers were separated and dried over anhydrous sodium sulfate. The crude product was obtained by evaporating the solvent. The crude product was purified using an ISCO combi-flash system (mobile phase: ethyl acetate:hexane gradient). 1.29 g of product was obtained (38.0% yield). C 10 Calculated MS(ESI) mass for H9NO2 is 175.18; [M+H] + The m / z value of was 176.1. Step 2: Synthesis of HBS-062-025: Compound HBS-062-022 (0.5 g, 2.85 mmol) and 1-aminopyridinium iodide (0.76 g, 3.43 mmol) were dissolved in anhydrous DMF (8.0 mL). Anhydrous K2CO3 (0.79 g, 5.71 mmol) was added, and the reaction mixture was stirred at ambient temperature for 16 hours. LCMS data indicated product formation (m / z value, 268.1). The rxn mixture was diluted with water, and the product was extracted with ethyl acetate. The combined ethyl acetate layers were separated and dried over anhydrous sodium sulfate. The crude product was obtained by evaporating the solvent. The crude product was purified using an ISCO combi-flash system (mobile phase: ethyl acetate:hexane gradient and DCM:methanol gradient). 0.57 g of product was obtained (74.6% yield). C 15 H 13 Calculated MS(ESI) mass for N3O2 is 267.28; [M+H] + The m / z value of was 268.1. Step 3: Synthesis of HBS-062-030: Compound HBS-062-025 (0.56 g, 2.1 mmol) was dissolved in MeOH (8.0 mL). 1.0 N aqueous NaOH solution (4.2 mL, 4.19 mmol) was added, and the reaction mixture was refluxed for 4 hours. LCMS showed product formation (m / z value, 240.1). The reaction mixture was concentrated under reduced pressure. The solid was dissolved in water and acidified with 2.0 M aqueous HCl (pH = 5). The precipitate was filtered and washed with water (2.0 mL x 3) to give 0.26 g of solid product (50.9% yield). 13 Calculated MS(ESI) mass for H9N3O2 is 239.23; [M+H] + The m / z value of was 240.1. [ka] Step 1: Synthesis of HBS-062-033: Ethyl 5-amino-1H-pyrazole-4-carboxylate (1.0 g, 6.43 mmol) and 1,1,3,3-tetraethoxypropane (1.85 mL, 7.72 mmol) were dissolved in acetic anhydride (8.0 mL). The reaction mixture was heated at 70 °C for 24 hours. LCMS data indicated product formation (m / z value, 192.1.0). The reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude product was diluted with water and neutralized with a saturated aqueous solution of NaHCO3. The product was extracted with DCM. The combined DCM layers were separated and dried over anhydrous sodium sulfate. The crude product was obtained by evaporating the solvent. The crude product was purified using an ISCO combi-flash system (mobile phase: DCM:methanol gradient). 0.98 g of product was obtained (79.7% yield). Calculated MS(ESI) mass for C9H9N3O2 is 191.19; [M+H] + The m / z value of was 192.1. Step 2: Synthesis of HBS-062-037: Compound HBS-062-033 (0.98 g, 5.13 mmol) was dissolved in DCM (15.0 mL). The reaction mixture was cooled to 0 °C in an ice bath. NBS (1.0 g, 5.64 mmol) was added, and the mixture was stirred at ambient temperature for 16 h. LCMS data indicated product formation (m / z value, 272.0). The reaction mixture was diluted with saturated aqueous NaHCO3. The product was extracted with DCM. The combined DCM layers were separated and dried over anhydrous sodium sulfate. Evaporation of the solvent gave 1.38 g of crude product (yield). MS (ESI) mass calculated for C9H8BrN3O2 was 270.08; [M+H] + The m / z value of was 272.0. Step 3: Synthesis of HBS-062-038: Compound HBS-062-037 (0.4 g, 1.48 mmol) and phenylboronic acid (0.27 g, 2.22 mmol) were dissolved in a mixture of dioxane / water (8:1 v / v mL). Anhydrous K2CO3 (0.61 g, 4.44 mmol) was added, followed by Pd(dppf)Cl2·DCM2 (0.06 g, 0.074 mmol). The rxn mixture was stirred at 100 °C under a nitrogen atmosphere for 6 hours. LCMS data indicated product formation (m / z value, 268.1). The rxn mixture was filtered through a Celite bed and washed with ethyl acetate. The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified using an ISCO combi-flash chromatography system (mobile phase: EtOAc:hexane gradient). 0.32 g of product was obtained (80.1% yield). C 15 H 13 Calculated MS(ESI) mass for N3O2 is 267.28; [M+H] + The m / z value of was 268.1. Step 4: Synthesis of HBS-062-041: Compound HBS-062-038 (0.32 g, 1.19 mmol) was dissolved in MeOH (5.0 mL). 1.0 N aqueous NaOH (2.4 mL, 2.37 mmol) was added, and the rxn mixture was refluxed for 6 hours. LCMS data indicated product formation (m / z value, 240.1). The rxn mixture was concentrated under reduced pressure and diluted with water. The aqueous layer was acidified with 2.0 M aqueous HCl (pH = 5). The precipitate was filtered and washed with water (2.0 mL x 3) to give 0.18 g of solid product (65.9% yield). C 13 Calculated MS(ESI) mass for H9N3O2 is 239.23; [M+H] + The m / z value of was 240.1. [ka] Step 1: Synthesis of HBS-039-013: Pyrazolo[1,5-a]pyridine-2-carboxylic acid (1.0 g, 6.17 mmol) was dissolved in ethanol (20.0 mL). A catalytic amount of concentrated sulfuric acid (0.5 mL) was added, and the rxn mixture was refluxed for 16 hours. LCMS data indicated product formation (m / z value, 191.1). The rxn mixture was concentrated under reduced pressure and neutralized with saturated aqueous sodium bicarbonate. The product was extracted with ethyl acetate. The ethyl acetate layer was separated and dried over anhydrous Na2SO4. The solvent was evaporated to give the product. (Yield) 1.2 g of product was obtained. C 10 H 10 Calculated MS(ESI) mass for N2O2 is 190.2; [M+H] + The m / z value of was 191.1. Step 2: Synthesis of HBS-039-014: HBS-039-013 (1.17 g, 6.17 mmol) was dissolved in DCM (25.0 mL). NBS (1.1 g, 6.17 mmol) was added, and the rxn mixture was stirred at ambient temperature for 16 hours. LCMS data indicated product formation (m / z value, 271.0). The rxn mixture was concentrated under reduced pressure to give the crude product. The crude product was purified using an ISCO combi-flash chromatography system (mobile phase: EtOAc:hexane gradient). 1.5 g of product was obtained (90.4% yield). C 10 Calculated MS(ESI) mass for H9BrN2O2 is 269.1; [M+H] + The m / z value of was 271.0. Step 3: Synthesis of HBS-062-179: Compound HBS-039-014 (0.5 g, 1.86 mmol) and 2-(tributylstannyl)-pyridine (1.36 g, 3.72 mmol) were dissolved in 1,4-dioxane (10.0 mL). Pd(PPh3)4 (0.214 g, 0.18 mmol) was added, and the reaction mixture was heated at 115 °C for 18 hours under a nitrogen atmosphere. LCMS data indicated product formation (m / z value, 268.0). The rxn mixture was filtered through a bed of Celite and washed with ethyl acetate. The filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified using an ISCO combi-flash chromatography system (mobile phase: EtOAc:hexane gradient). 0.35 g of product was obtained (70.5% yield).15 H 13 Calculated MS(ESI) mass for N3O2 is 267.28; [M+H] + The m / z value of was 268.0. Step 4: Synthesis of HBS-062-182: Compound HBS-062-179 (0.35 g, 1.31 mmol) was dissolved in MeOH (5.0 mL). 1.0 N aqueous NaOH (2.62 mL, 2.62 mmol) was added, and the rxn mixture was refluxed for 8 hours. LCMS data indicated product formation (m / z value, 240.1). The rxn mixture was concentrated under reduced pressure and diluted with water. The aqueous layer was acidified with 2.0 M aqueous HCl (pH = 5). The precipitate was filtered and washed with water (2.0 mL x 3) to give 0.31 g of product (yield). C 13 Calculated MS(ESI) mass for H9N3O2 is 239.23; [M+H] + The m / z value of was 240.1. [ka] Step 1: Synthesis of HBS-062-033: Ethyl 5-amino-1H-pyrazole-4-carboxylate (1.0 g, 6.43 mmol) and 1,1,3,3-tetraethoxypropane (1.85 mL, 7.72 mmol) were dissolved in acetic anhydride (8.0 mL). The reaction mixture was heated at 70 °C for 24 hours. LCMS data indicated product formation (m / z value, 192.1.0). The reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude product was diluted with water and neutralized with a saturated aqueous solution of NaHCO3. The product was extracted with DCM. The combined DCM layers were separated and dried over anhydrous sodium sulfate. The crude product was obtained by evaporating the solvent. The crude product was purified using an ISCO combi-flash system (mobile phase: DCM:methanol gradient). 0.98 g of product was obtained (79.7% yield). Calculated MS(ESI) mass for C9H9N3O2 is 191.19; [M+H] + The m / z value of was 192.1. Step 2: Synthesis of HBS-062-037: Compound HBS-062-033 (0.98 g, 5.13 mmol) was dissolved in DCM (15.0 mL). The reaction mixture was cooled to 0 °C in an ice bath. NBS (1.0 g, 5.64 mmol) was added, and the mixture was stirred at ambient temperature for 16 h. LCMS data showed product formation (m / z value, 272.0). The reaction mixture was diluted with saturated aqueous NaHCO3. The product was extracted with DCM. The combined DCM layers were separated and dried over anhydrous sodium sulfate. Evaporation of the solvent gave 1.38 g of crude product (yield). MS (ESI) mass calculated for C9H8BrN3O2 was 270.08; [M+H] + The m / z value of was 272.0. Step 3: Synthesis of HBS-062-183: Compound HBS-062-037 (0.95 g, 3.52 mmol) and 2-(tributylstannyl)-pyridine (1.94 g, 5.28 mmol) were dissolved in 1,4-dioxane (12.0 mL). Pd(PPh3)4 (0.41 g, 0.35 mmol) was added, and the reaction mixture was heated at 115 °C for 18 hours under a nitrogen atmosphere. 0.05 equivalents of Pd(PPh3)4 was added to consume the starting material. LCMS data indicated product formation (m / z value, 269.0). The rxn mixture was filtered through a bed of Celite and washed with ethyl acetate. The filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified using an ISCO combi-flash chromatography system (mobile phase: EtOAc:hexane gradient). 0.725 g of product was obtained (76.8% yield). 14 H 12 Calculated MS(ESI) mass for N4O2 is 268.27; [M+H] + The m / z value of was 269.0. Step 4: Synthesis of HBS-062-186: Compound HBS-062-183 (0.73 g, 2.7 mmol) was dissolved in MeOH (8.0 mL). 1.0 N aqueous NaOH (5.4 mL, 5.4 mmol) was added, and the rxn mixture was refluxed for 6 hours. LCMS data indicated product formation (m / z value, 241.1). The rxn mixture was concentrated under reduced pressure and diluted with water. The aqueous layer was acidified with 2.0 M aqueous HCl (pH = 5). The precipitate was filtered and washed with water (2.0 mL x 3) to give 0.52 g of product (80.2% yield). C 12 Calculated MS(ESI) mass for H8N4O2 is 240.22; [M+H] + The m / z value of was 241.1. [ka] Step 1: Synthesis of HBS-062-173: Ethyl 5-hydroxy-1H-pyrazole-3-carboxylate (2.0 g, 12.81 mmol) was dissolved in anhydrous acetonitrile (40.0 mL). Anhydrous K2CO3 (7.1 g, 51.24 mmol) was added, and the reaction mixture was stirred at ambient temperature for 10 minutes. 1,3-Dibromopropane (1.43 mL, 14.1 mmol) was added, and the reaction mixture was heated at reflux for 12 hours. LCMS data indicated product formation (m / z value, 197.1). The reaction mixture was cooled to ambient temperature and filtered through Celite. The filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified using an ISCO combi-flash chromatography system (mobile phase: EtOAc:hexane gradient). 1.93 g of product was obtained (76.8% yield). CH 12 Calculated MS(ESI) mass for N2O3 is 196.20; [M+H] + The m / z value of was 197.1. Step 2: Synthesis of HBS-062-178: Compound HBS-062-173 (1.9 g, 9.68 mmol) was dissolved in DCM (30.0 mL). NIS (2.61 g, 11.62 mmol) was added, and the resulting mixture was stirred at ambient temperature for 30 hours. 0.6 equivalents of NIS was added to consume the starting material. LCMS data indicated product formation (m / z value, 323.0). The reaction mixture was diluted with water, and the product was extracted with DCM. The DCM layer was separated and washed with aqueous sodium thiosulfate. The combined DCM layers were separated and dried over anhydrous sodium sulfate. The crude product was obtained by evaporating the solvent. The crude product was purified using an ISCO combi-flash system (mobile phase: EtOAc:hexane gradient). Yield: 3.12 g of product. CH 11 Calculated MS(ESI) mass for IN2O3 is 322.1; [M+H] + The m / z value of was 323.0. Step 3: Synthesis of HBS-062-189: Compound HBS-062-178 (1.0 g, 3.11 mmol) and 2-(tributylstannyl)-pyridine (1.14 g, 3.11 mmol) were dissolved in 1,4-dioxane (12.0 mL). Pd(PPh3)4 (0.36 g, 0.31 mmol) was added, and the reaction mixture was heated at 120 °C under a nitrogen atmosphere for 30 hours. LCMS data indicated product formation (m / z value, 274.0). The rxn mixture was filtered through a Celite bed and washed with ethyl acetate. The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified using an ISCO combi-flash chromatography system (mobile phase: EtOAc:hexane gradient and EtOAc:methanol (95:05, v / v mL) gradient). 0.44 g of product was obtained (51.9% yield). 14 H 15 Calculated MS(ESI) mass for N3O3 is 273.3; [M+H] + The m / z value of was 274.0. Step 4: Synthesis of HBS-062-192: Compound HBS-062-189 (0.44 g, 1.61 mmol) was dissolved in MeOH (8.0 mL). 1.0 N aqueous NaOH (3.22 mL, 3.22 mmol) was added, and the rxn mixture was refluxed for 8 hours. LCMS data indicated product formation (m / z value, 246.1). The rxn mixture was concentrated under reduced pressure and diluted with water. The aqueous layer was acidified with 2.0 M aqueous HCl (pH = 5). The precipitate was filtered and washed with water (2.0 mL x 3) to give 0.31 g of product (78.5% yield). C 12 H 11 Calculated MS(ESI) mass for N3O3 is 245.23; [M+H] + The m / z value of was 246.1. [ka] Step 1: Synthesis of HBS-062-199: 3-Bromoimidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester (1.0 g, 3.72 mmol) and 2-(tributylstannyl)-pyridine (1.5 g, 4.1 mmol) were dissolved in dry DMF (12.0 mL). Pd(PPh3)4 (0.43 g, 0.37 mmol) was added, and the reaction mixture was heated at 115-120 °C for 36 h under a nitrogen atmosphere. 0.05 equivalents of Pd(PPh3)4 were added, and the starting material was consumed during the reaction. LCMS data showed the product (m / z, 268.1) and the acid byproduct (m / z, 240.1). The reaction mixture was diluted with water, and the product was extracted with DCM. The DCM layer was separated and washed with aqueous sodium thiosulfate. The combined DCM layers were separated and dried over anhydrous sodium sulfate. The crude product was obtained by evaporating the solvent. The crude product was purified using an ISCO combi-flash chromatography system (mobile phase: EtOAc:hexane gradient and EtOAc:methanol (95:05, v / v mL) gradient). 0.61 g of product was obtained (61.4% yield). 15 H 13 Calculated MS(ESI) mass for N3O2 is 267.28; [M+H] + The m / z value of was 268.1. 0.1 g of the acid by-product was obtained (yield 11.2%). 13Calculated MS(ESI) mass for H9N3O2 is 239.23; [M+H] + The m / z value of was 240.1. Step 2: Synthesis of HBS-065-004: Compound HBS-062-199A (0.61 g, 2.28 mmol) was dissolved in MeOH (8.0 mL). 1.0 N aqueous NaOH (4.6 mL, 4.56 mmol) was added, and the reaction mixture was refluxed for 8 hours. LCMS data indicated product formation (m / z value, 240.9). The rxn mixture was concentrated under reduced pressure and diluted with water. The aqueous layer was acidified with 2.0 M aqueous HCl (pH = 5). The aqueous layer was concentrated to give 0.55 g of product (yield). 13 Calculated MS(ESI) mass for H9N3O2 is 239.23; [M+H] + The m / z value of was 240.9. [ka] Step 1: Synthesis of HBS-065-011: HBS-062-010 (1.0 g, 3.64 mmol) and 2-(tributylstannyl)-pyridine (1.6 g, 4.36 mmol) were dissolved in dry DMF (12.0 mL). Pd(PPh3)4 (0.42 g, 0.36 mmol) was added, and the reaction mixture was heated at 120 °C for 30 h under a nitrogen atmosphere. 0.05 equivalents of Pd(PPh3)4 were added, and the starting material was consumed during the reaction. LCMS data showed product formation (m / z value, 274.0) and an acid by-product (m / z value, 246.0). The reaction mixture was diluted with water, and the product was extracted with DCM. The DCM layer was separated and washed with aqueous sodium thiosulfate. The combined DCM layers were separated and dried over anhydrous sodium sulfate. The crude product was obtained by evaporating the solvent. The crude product was purified on an ISCO combi-flash chromatography system (mobile phase: EtOAc:hexane gradient and DCM:methanol gradient). 0.26 g of product was obtained (yield 26.3%). 14 H 15 Calculated MS(ESI) mass for N3O3 is 273.29; [M+H] + The m / z value of was 274.0. 0.15 g of the acid by-product was obtained (yield 16.8%).12 H 11 Calculated MS(ESI) mass for N3O3 is 245.23; [M+H] + The m / z value of was 246.0. Step 2: Synthesis of HBS-065-019: Compound HBS-065-011A (0.26 g, 0.96 mmol) was dissolved in MeOH (5.0 mL). 1.0 N aqueous NaOH (1.9 mL, 1.91 mmol) was added, and the reaction mixture was refluxed for 3 hours. LCMS data indicated product formation (m / z value, 246.1). The rxn mixture was concentrated under reduced pressure and diluted with water. The aqueous layer was acidified with 2.0 M aqueous HCl (pH = 5). The precipitate was filtered, and the aqueous layer was concentrated to give 0.23 g of the total product (92.0% yield). 12 H 11 Calculated MS(ESI) mass for N3O3 is 245.23; [M+H] + The m / z value of was 246.1. [ka] Step 1: Synthesis of HBS-065-050: Ethyl picolinoylacetate (0.5 g, 2.59 mmol) was dissolved in chloroform (12.0 mL). A solution of bromine (0.13 mL, 2.59 mmol) in chloroform (1.0 mL) was added, and the reaction mixture was stirred at ambient temperature for 2 hours. LCMS showed product formation (m / z value, 274.0). The reaction mixture was diluted with saturated aqueous NaHCO3, and the product was extracted with chloroform. The chloroform layer was separated and dried over anhydrous Na2SO4. Evaporation of the solvent gave 0.7 g of crude product (yield). C 10 H 10 Calculated MS(ESI) mass for BrNO3 is 272.1; [M+H] + The m / z value of was 274.0. Step 2: Synthesis of HBS-065-051: Compound HBS-065-050 (0.7 g, 2.59 mmol) was dissolved in anhydrous acetonitrile (8.0 mL). 2-Amino-5-fluoropyridine (0.29 g, 2.59 mmol) was added, and the reaction mixture was heated at reflux for 16 hours. LCMS showed product formation (m / z value, 286.1). The reaction mixture was diluted with saturated aqueous NaHCO3, and the product was extracted with ethyl acetate. The combined ethyl acetate layers were separated and dried over anhydrous sodium sulfate. The crude product was obtained by evaporating the solvent. The crude product was purified using a combi-flash system (mobile phase: DCM:methanol gradient). 0.39 g of product was obtained (yield 52.8%). C 15 H 12 Calculated MS(ESI) mass for FN3O2 is 285.27; [M+H] + The m / z value of was 286.1. Step 3: Synthesis of HBS-065-055: Compound HBS-065-051 (0.39 g, 1.37 mmol) was dissolved in MeOH (8.0 mL). 1.0 N aqueous NaOH solution (2.7 mL, 2.73 mmol) was added, and the reaction mixture was heated at reflux for 12 hours. LCMS showed product formation (m / z value, 258.2). The reaction mixture was concentrated under reduced pressure. The solid was dissolved in water and acidified with 2.0 M aqueous HCl (pH = 5). The precipitate was filtered and washed with water (2.0 mL x 3) to give 0.33 g of solid product (93.8% yield). 13 Calculated MS(ESI) mass for H8FN3O2 is 257.22; [M+H] + The m / z value of was 258.2. [ka] Step 1: Synthesis of HBS-065-062: Compound HBS-065-050 (1.41 g, 5.18 mmol) was dissolved in anhydrous acetonitrile (10.0 mL). 2-Amino-4-chloropyridine (0.67 g, 5.18 mmol) was added, and the reaction mixture was heated at reflux for 16 hours. LCMS showed product formation (m / z value, 302.0). The reaction mixture was diluted with saturated aqueous NaHCO3, and the product was extracted with ethyl acetate. The combined ethyl acetate layers were separated and dried over anhydrous sodium sulfate. The crude product was obtained by evaporating the solvent. The crude product was purified using a combi-flash system (mobile phase: DCM:methanol gradient). 0.8 g of product was obtained (yield 51.2%). C 15 H 12 Calculated MS(ESI) mass for ClN3O2 is 301.73; [M+H] + The m / z value of was 302.0. Step 2: Synthesis of HBS-065-064: Compound HBS-065-062 (0.8 g, 2.65 mmol) was dissolved in MeOH (8.0 mL). 1.0 N aqueous NaOH solution (5.3 mL, 5.30 mmol) was added, and the reaction mixture was heated at reflux for 8 hours. LCMS showed product formation (m / z value, 274.0). The reaction mixture was concentrated under reduced pressure. The crude product was dissolved in water and acidified with 2.0 M aqueous HCl (pH = 5). The precipitate was filtered and washed with water (3.0 mL x 3) to give 0.46 g of solid product (63.4% yield). 13 Calculated MS(ESI) mass for H8ClN3O2 is 273.67; [M+H] + The m / z value of was 274.0. [ka] Step 1: Synthesis of HBS-065-073: Compound HBS-065-050 (1.41 g, 5.18 mmol) was dissolved in anhydrous acetonitrile (12.0 mL). 2-Aminopyridine (0.49 g, 5.18 mmol) was added, and the reaction mixture was heated at reflux for 16 hours. LCMS showed product formation (m / z value, 268.0). The reaction mixture was diluted with saturated aqueous NaHCO3, and the product was extracted with ethyl acetate. The combined ethyl acetate layers were separated and dried over anhydrous sodium sulfate. The crude product was obtained by evaporating the solvent. The crude product was purified using a combi-flash system (mobile phase: DCM:methanol gradient). 0.7 g of product was obtained (yield 50.6%). C 15 H 13 Calculated MS(ESI) mass for N3O2 is 267.28; [M+H] + The m / z value of was 268.0. Step 2: Synthesis of HBS-065-076: Compound HBS-065-073 (0.7 g, 2.62 mmol) was dissolved in MeOH (6.0 mL). 1.0 N aqueous NaOH solution (5.2 mL, 5.24 mmol) was added, and the reaction mixture was heated at reflux for 4 hours. LCMS showed product formation (m / z value, 240.0). The reaction mixture was concentrated under reduced pressure. The crude product was dissolved in water and acidified with 2.0 M aqueous HCl (pH = 5). The precipitate was filtered and washed with water (3.0 mL x 3) to give 0.52 g of solid product (83.0% yield). 13 Calculated MS(ESI) mass for H9N3O2 is 239.23; [M+H] + The m / z value of was 240.0. [ka] Step 1: Synthesis of HBS-065-106: Pyrazolo[1,5-a]pyridine-2-carboxylic acid (2.0 g, 12.34 mmol) was dissolved in ethanol (40.0 mL). A catalytic amount of concentrated sulfuric acid (0.1 mL) was added, and the rxn mixture was refluxed for 8 hours. LCMS data showed product formation (m / z value, 191.1). The rxn mixture was concentrated under reduced pressure and neutralized with saturated aqueous sodium bicarbonate. The product was extracted with ethyl acetate. The ethyl acetate layer was separated and dried over anhydrous Na2SO4. The solvent was evaporated to give the product. 2.2 g of product was obtained (yield 93.7%). C 10 H 10 Calculated MS(ESI) mass for N2O2 is 190.2; [M+H] + The m / z value of was 191.1. Step 2: Synthesis of HBS-065-108: Compound HBS-065-106 (2.2 g, 11.57 mmol) was dissolved in DCM (40.0 mL). NBS (2.27 g, 12.73 mmol) was added, and the rxn mixture was stirred at ambient temperature for 16 hours. LCMS data indicated product formation (m / z value, 270.9). The rxn mixture was diluted with saturated aqueous sodium bicarbonate. The product was extracted with DCM. The combined DCM layers were separated and dried over anhydrous Na2SO4. The solvent was evaporated to give the product. The crude product was purified using a normal phase chromatography system (mobile phase: EtOAc:hexane gradient). Yield: 3.11 g of product was obtained. C 10 Calculated MS(ESI) mass for H9BrN2O2 is 269.1; [M+H] + The m / z value of was 270.9. Step 3: Synthesis of HBS-065-125: Compound HBS-065-108 (0.4 g, 1.49 mmol) and 5-chlorothiophene-2-boronic acid (0.48 g, 2.97 mmol) were dissolved in a mixture of dioxane and water (12:1 v / v mL). Anhydrous K2CO3 (0.41 g, 2.97 mmol) was added, followed by Pd(dppf)Cl2·DCM2 (0.06 g, 0.074 mmol). The rxn mixture was stirred at 100 °C for 24 hours under a nitrogen atmosphere. 5-Chlorothiophene-2-boronic acid and a catalyst were added, and the starting material was consumed during the reaction. LCMS data indicated product formation (m / z value, 307.0). The rxn mixture was filtered through a Celite bed and washed with ethyl acetate. The filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by ISCO combi-flash chromatography system (mobile phase: EtOAc:hexane gradient). 0.31 g of product was obtained (yield 67.9%). 14 H 11 Calculated MS(ESI) mass for ClN2O2S is 306.77; [M+H] + The m / z value of was 307.0. Step 4: Synthesis of HBS-065-127: Compound HBS-065-125 (0.31 g, 1.01 mmol) was dissolved in MeOH (5.0 mL). 1.0 N aqueous NaOH solution (2.0 mL, 2.0 mmol) was added, and the reaction mixture was stirred at ambient temperature for 16 hours. LCMS data indicated product formation (m / z value, 278.9). The rxn mixture was concentrated under reduced pressure and diluted with water. The aqueous layer was acidified with 2.0 M aqueous HCl solution (pH = 5). The precipitate was filtered and washed with water (2.0 mL x 3) to give 0.24 g of solid product (83.4% yield). C 12 Calculated MS(ESI) mass for H7ClNO2S is 278.71; [M+H] + The m / z value of was 278.9. [ka] Step 1: Synthesis of HBS-065-156: Compound HBS-065-108 (0.5 g, 1.86 mmol) and 2-(tributylstannyl)-pyrimidine (0.69 g, 1.86 mmol) were dissolved in anhydrous DMF (6.0 mL). Anhydrous CsF (0.85 g, 5.57 mmol) and CuCl (0.024 g, 0.24 mmol) were added, followed by Pd(PPh3)4 (0.11 g, 0.093 mmol). The rxn mixture was irradiated in a microwave reactor at 120 °C for 50 minutes. LCMS data indicated product formation (m / z value, 269.2). The rxn mixture was filtered through a Celite bed and washed with ethyl acetate. The filtrate was diluted with water and extracted with ethyl acetate. The combined ethyl acetate layers were separated and dried over anhydrous Na2SO4. The crude product was obtained by evaporating the solvent. The crude product was purified by ISCO combi-flash chromatography system (mobile phase: EtOAc:hexane gradient). 0.37 g of product was obtained (73.6% yield). 14 H 12 Calculated MS(ESI) mass for N4O2 is 268.27; [M+H] + The m / z value of was 269.2. Step 2: Synthesis of HBS-065-159: Compound HBS-065-156 (0.37 g, 1.37 mmol) was dissolved in MeOH (8.0 mL). 1.0 N aqueous NaOH solution (2.74 mL, 2.74 mmol) was added, and the reaction mixture was refluxed for 4 hours. LCMS data indicated product formation (m / z value, 241.1). The rxn mixture was concentrated under reduced pressure and diluted with water. The aqueous layer was acidified with 2.0 M aqueous HCl solution (pH = 5). The precipitate was filtered and washed with water (2.0 mL x 3) to give 0.25 g of solid product (76.7% yield). 12 Calculated MS(ESI) mass for H8N4O2 is 240.22; [M+H] + The m / z value of was 241.1. [ka] Step 1: Synthesis of HBS-039-126: Ethyl benzoylacetate (0.5 g, 2.6 mmol) was dissolved in anhydrous acetonitrile (10.0 mL). 2-Aminopyrimidine (0.55 g, 5.76 mmol) was added, followed by CBr4 (1.27 g, 3.84 mmol), and the reaction mixture was stirred at 80° C. for 48 hours. Reagents were added to consume the starting material. LCMS showed product formation (m / z value, 268.1). The reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified using a combi-flash system (mobile phase: EtOAc:hexane gradient). 0.15 g of product was obtained (21.3% yield). C 15 H 13 Calculated MS(ESI) mass for N3O2 is 267.28; [M+H] + The m / z value of was 268.1. Step 2: Synthesis of HBS-039-132: Compound HBS-039-126 (0.15 g, 0.55 mmol) was dissolved in MeOH (2.5 mL). 1.0 N aqueous NaOH solution (2.77 mL, 2.76 mmol) was added, and the reaction mixture was refluxed for 3 hours. LCMS showed product formation (m / z value, 240.1). The reaction mixture was concentrated under reduced pressure. The solid was dissolved in water and acidified with 2.0 M aqueous HCl (pH = 5). The precipitate was filtered and washed with water (2.0 mL x 3) to give 0.11 g of solid product (82.7% yield). 13 Calculated MS(ESI) mass for H9N3O2 is 239.23; [M+H] + The m / z value of was 240.1.

[0054] Synthesis of Secondary Amine-Containing Intermediates - Amine Group [ka] Step 1: Synthesis of HBS-061-186: The carboxylic acid (1.540 g, 6.72 mmol) was dissolved in THF (30 mL). The solution was cooled in an ice bath for 1 h. CDI (1.09 g, 6.72 mmol) was added, and 30 min later, the ice bath was removed and the reaction was stirred at room temperature for 18 h. Hydroxylamidine (0.694 g, 4.48 mmol) was added and continued stirring at room temperature. After 24 h, LCMS showed only 36% conversion to the acyl intermediate. HOBT (0.908 g, 6.72 mmol), EDC (1.09 g, 6.72 mmol), and TEA (3.11 mL, 22.3 mmol), and CHCl (30 mL) were added sequentially and stirred at room temperature. LCMS showed complete conversion to the acyl intermediate (m / z value, 367) after 22 h. The acyl intermediate was isolated by extractive workup with EtOAc and water to give a viscous yellow oil (2.40 g). This oil was dissolved in DCM (15 mL), toluene (25 mL) was added, and the reaction was heated to 100-120 °C in an open flask. LCMS showed the desired product (m / z value, 349). The reaction mixture was dissolved in a saturated aqueous solution of NaHCO3 and extracted with EtOAc. The EtOAc layer was dried over Na2SO4, filtered, and evaporated. The crude product was purified by column chromatography (mobile phase: hexane:EtOAc gradient). 1.14 g of a white solid was obtained (yield = 73.3%). 17 H 21 Calculated MS(ESI) mass for FN4O3 is 348.2; [M+H] + The m / z value of was 349.1. Step 2: Synthesis of HBS-061-199: Compound HBS-061-186 (1.142 g, 3.28 mmol) was dissolved in anhydrous dioxane (20 mL). 4.0 M HCl in dioxane (4.1 mL, 16.4 mmol) was added, and the reaction was stirred vigorously at 60° C. for 42 hours to form a suspension. LCMS showed complete conversion to the product (m / z value, 249). The reaction mixture was cooled to room temperature, filtered, and washed with hexane to give a paste that adhered to the filter paper. This sample was dissolved in MeOH, concentrated, and then dried in a vacuum oven to give 0.807 g of a powdery off-white solid (yield=76.7%). 12 H 13 Calculated MS(ESI) mass for FNO is 248.1; [M+H] + The m / z value of was 249.1. [ka] Step 1: Synthesis of HBS-061-180: The carboxylic acid (1.993 g, 8.69 mmol) was dissolved in THF (40 mL). The solution was cooled in an ice bath for 1 h. CDI (1.42 g, 8.76 mmol) was added 15 min later, the ice bath was removed, and the reaction was stirred at room temperature for 6 h. Hydroxylamidine (0.795 g, 5.80 mmol) was added and stirring continued at room temperature. After 72 h, LCMS showed only 50% conversion to the acyl intermediate. HOBT (1.17 g, 8.66 mmol), EDC (1.67 g, 8.71 mmol), TEA (4.0 mL, 28.7 mmol), and CHCl (40 mL) were added sequentially and stirred at room temperature. LCMS showed complete conversion to the acyl intermediate (m / z value, 349) after 22 h. The acyl intermediate was isolated by workup with EtOAc and water extraction to give a pale yellow oil (2.87 g). This oil was dissolved in CHCl (25 mL), toluene (30 mL) was added, and the reaction was heated to 100° C. in an open flask. LCMS showed product formation (m / z value, 331). The reaction mixture was dissolved in a saturated aqueous solution of NaHCO and extracted with EtOAc. The EtOAc layer was dried over NaSO, filtered, and evaporated. The crude product was purified by column chromatography (mobile phase: hexane:EtOAc gradient). 1.65 g of a colorless oil was obtained (yield=85.9%). 17 H 22 Calculated MS(ESI) mass for N4O3 is 330.2; [M+H] + The m / z value of was 331.1. Step 2: Synthesis of HBS061-198: Compound HBS-061-180 (1.645 g, 4.98 mmol) was dissolved in anhydrous dioxane (30 mL). 4.0 M HCl in dioxane (6.2 mL, 24.8 mmol) was added, and the reaction was stirred vigorously at 60° C. for 42 hours. LCMS showed complete conversion to the product (m / z value, 231). The reaction mixture was cooled to room temperature, filtered, and washed with hexane to give a paste that adhered to the filter paper. This sample was dissolved in MeOH, concentrated, and then dried in a vacuum oven to give 1.47 g of a beige, hard solid (yield=97.1%). 12 H14 Calculated MS(ESI) mass for NO is 230.1; [M+H] + The m / z value of was 231.1. [ka] General synthesis of HBS-061-129: The alcohol (3.09 g, 14.3 mmol) was dissolved in anhydrous DCM (30 mL). DIPEA (3.75 mL, 21.5 mmol) and DMAP (2.63 g, 21.5 mmol) were added sequentially, and the mixture was stirred in an ice bath for 1 h. p-TsCl (3.01 g, 15.8 mmol) was added portionwise over 20 min, and the ice bath was allowed to warm slowly to room temperature over 24 h. The starting material was consumed during the reaction by adding reagents. LCMS data indicated product formation (m / z values, 314, 270). The reaction mixture was treated with water, and the product was extracted with DCM. The DCM layer was dried over Na2SO4, filtered, and evaporated. The crude product was purified by column chromatography (mobile phase: hexane: EtOAc gradient). 3.21 g of a crystalline white solid was obtained (yield = 60.4%). C 18 H 27 Calculated MS(ESI) mass for NO5S is 369.2; [M+H] + The m / z values ​​were 314.1 and 270.1. Step 1: Synthesis of HBS-061-132: HBS-061-129 (1.034 g, 2.80 mmol) and pyrazole (0.716 g, 3.36 mmol) were dissolved in anhydrous dioxane (20 mL). CsCO (1.82 g, 5.58 mmol) was added, and the reaction mixture was heated to 70 °C with vigorous stirring. LCMS revealed high conversion to the product as an 82:18 isomeric mixture (m / z value after 40 h, 411). The reaction mixture was cooled to room temperature, treated with water, and extracted with EtOAc. The EtOAc layer was dried over NaSO, filtered, and evaporated. The crude product was purified by column chromatography (mobile phase: hexane: EtOAc gradient). 0.39 g of the major isomer was obtained as a colorless oil (yield = 33.7%). 20 H 25 Calculated MS(ESI) mass for F3N4O2 is 410.2; [M+H]+ The m / z value of was 411.2. Step 2: Synthesis of HBS-061-140: Compound HBS-061-132 (0.387 g, 0.943 mmol) was dissolved in anhydrous dioxane (7 mL). 4.0 M HCl in dioxane (1.2 mL, 4.8 mmol) was added, and the reaction was stirred vigorously at 50° C. for 21 hours. LCMS showed complete conversion to the product (m / z value, 311). The reaction mixture was cooled to room temperature and concentrated to give a glass. This sample was dissolved in MeOH, concentrated, and then dried in a vacuum oven to give 0.38 g of glass (yield). 15 H 17 Calculated MS(ESI) mass for F3N4 is 310.2; [M+H] + The m / z value of was 311.2. [ka] Step 1: Synthesis of HBS-061-133: Compound HBS-061-129 (1.050 g, 2.84 mmol) and pyrazole (0.612 g, 3.41 mmol) were dissolved in anhydrous dioxane (20 mL). CsCO (1.85 g, 5.68 mmol) was added, and the reaction mixture was heated to 70 °C with vigorous stirring. LCMS revealed high conversion to the product as an 80:20 mixture of isomers (m / z value after 40 h, 377). The reaction mixture was cooled to room temperature, treated with water, and extracted with EtOAc. The EtOAc layer was dried over NaSO, filtered, and evaporated. The crude product was purified by column chromatography (mobile phase: hexane: EtOAc gradient). 0.35 g of the major isomer was obtained as a colorless oil (yield = 32.3%). 19 H 25 Calculated MS(ESI) mass for ClNO is 376.2; [M+H] + The m / z value of was 377.2. Step 2: Synthesis of HBS-061-141: Compound HBS-061-133 (0.346 g, 0.918 mmol) was dissolved in anhydrous dioxane (7 mL). 4.0 M HCl in dioxane (1.15 mL, 4.6 mmol) was added, and the reaction was vigorously stirred at 50° C. for 24 hours, then at 60° C. for an additional 3 hours. LCMS showed complete conversion to the product (m / z value, 277). The reaction mixture was cooled to room temperature, filtered, and washed with hexane to give 0.27 g of a powdery white solid (yield=85.3%). 14 H 17 Calculated MS(ESI) mass for ClN4 is 276.1; [M+H] + The m / z value of was 277.1. [ka] Step 1: Synthesis of HBS-061-134: Compound HBS-061-129 (1.011 g, 2.74 mmol) and pyrazole (0.612 g, 3.41 mmol) were dissolved in anhydrous dioxane (20 mL). CsCO (1.78 g, 5.46 mmol) was added, and the reaction mixture was heated to 70 °C with vigorous stirring. LCMS revealed high conversion to the product as an 88:12 isomeric mixture (m / z value after 40 h, 412). The reaction mixture was cooled to room temperature, treated with water, and extracted with EtOAc. The EtOAc layer was dried over NaSO, filtered, and evaporated. The crude product was purified by column chromatography (mobile phase: hexane: EtOAc gradient). 0.30 g of the major isomer was obtained as a colorless oil (yield = 26.9%). 19 H 24 Calculated MS(ESI) mass for F3N5O2 is 411.2; [M+H] + The m / z value of was 412.1. Step 2: Synthesis of HBS-061-142: Compound HBS-061-134 (0.303 g, 0.736 mmol) was dissolved in anhydrous dioxane (7 mL). 4.0 M HCl in dioxane (0.92 mL, 3.7 mmol) was added, and the reaction was vigorously stirred at 50° C. for 24 hours, then at 60° C. for an additional 3 hours. LCMS showed complete conversion to the product (m / z value, 312). A precipitate formed upon cooling. The reaction mixture was filtered and washed with hexane to give 0.23 g of a powdery white solid (yield=79.9%). 14 H 16 Calculated MS(ESI) mass for F3N5 is 311.1; [M+H] + The m / z value of was 312.2. [ka] Synthesis of HBS-061-169: The alcohol (3.02 g, 15.0 mmol) was dissolved in anhydrous CHCl (32 mL). DIPEA (3.92 mL, 22.5 mmol) and DMAP (2.75 g, 22.5 mmol) were added sequentially, and the mixture was stirred in an ice bath for 1 h. p-TsCl (3.43 g, 15.8 mmol) was added portionwise over 10 min, and the ice bath was allowed to warm slowly to room temperature. After 24 h at room temperature, LCMS revealed complete conversion of the product (m / z values ​​300, 256). The reaction mixture was treated with water, and the product was extracted with DCM. The DCM layer was dried over NaSO, filtered, and evaporated. The crude product was purified by column chromatography (mobile phase: hexane: EtOAc gradient). 4.91 g of a colorless oil was obtained (yield = 92.0%). C 17 H 25 Calculated MS(ESI) mass for NO5S is 355.2; [M+H] + The m / z values ​​were 300.0 and 256.0. [ka] Step 1: Synthesis of HBS-061-146: Compound HBS-061-169 (1.533 g, 4.31 mmol) and pyrazole (0.750 g, 5.17 mmol) were dissolved in anhydrous dioxane (30 mL). CsCO (2.81 g, 5.17 mmol) was added, and the reaction mixture was heated to 100 °C with vigorous stirring. LCMS revealed high conversion to the product as an 83:17 mixture of isomers (m / z value after 24 h, 329). The reaction mixture was cooled to room temperature, treated with water, and extracted with EtOAc. The EtOAc layer was dried over NaSO, filtered, and evaporated. The crude product was purified by column chromatography (mobile phase: hexane: EtOAc gradient). 1.06 g of the major isomer was obtained as a colorless oil (yield = 75.0%). 18 H 24 Calculated MS(ESI) mass for N4O2 is 328.2; [M+H] + The m / z value of was 329.2. Step 2: Synthesis of HBS-061-153: Compound HBS-061-146 (1.061 g, 3.23 mmol) was dissolved in anhydrous dioxane (12 mL). 4.0 M HCl in dioxane (4.04 mL, 16.2 mmol) was added, and the reaction was vigorously stirred at 60° C. for 18 hours. LCMS showed complete conversion to the product (m / z value, 229). The reaction mixture was cooled to room temperature, filtered, and washed with hexane to give 0.97 g of a powdery white solid (yield=100%). 13 H 16 Calculated MS(ESI) mass for N4 is 228.1; [M+H] + The m / z value of was 229.1. [ka] Step 1: Synthesis of HBS-061-167: Alcohol (1.41 g, 7.0 mmol) was dissolved in anhydrous THF (10 mL). 60% NaH (0.42 g, 10.5 mmol) was added portionwise, followed after 15 min by the addition of a solution of chloropyrimidine (1.28 g, 7.00 mmol) in DMF (6 mL). The reaction mixture was heated to 70 °C. LCMS showed product formation (m / z values ​​after 3 h: 292, 248). The reaction mixture was cooled to room temperature, treated with water, and extracted with EtOAc. The EtOAc layer was dried over Na2SO4, filtered, and evaporated. The crude product was purified by column chromatography (mobile phase: hexane: EtOAc gradient). 0.13 g of product was obtained as a colorless oil (yield = 5.3%). C 15 H 20 Calculated MS(ESI) mass for F3N3O3 is 347.2; [M+H] + The m / z values ​​were 292.0 and 248.1. Step 2: Synthesis of HBS-061-170: Compound HBS-061-167 (0.129 g, 0.371 mmol) was dissolved in anhydrous dioxane (2 mL). 4.0 M HCl in dioxane (0.47 mL, 1.88 mmol) was added, and the reaction was stirred vigorously at room temperature for 96 hours to form a suspension. LCMS showed complete conversion to the product (m / z value, 248). The reaction mixture was filtered and washed with hexane to give 67 mg of a white solid (yield = 63.5%). 10 H 12 Calculated MS(ESI) mass for FNO is 247.1; [M+H] + The m / z value of was 248.1. [ka] Step 1: Synthesis of HBS-061-185: Compound HBS-061-169 (0.695 g, 1.96 mmol) and pyrazole (0.422 g, 2.35 mmol) were dissolved in anhydrous dioxane (15 mL). CsCO (1.27 g, 3.90 mmol) was added, and the reaction mixture was heated to 100 °C with vigorous stirring. LCMS revealed high conversion to the product as a mixture of isomers (m / z value after 42 h, 363). The reaction mixture was cooled to room temperature, treated with water, and extracted with EtOAc. The EtOAc layer was dried over NaSO, filtered, and evaporated. The crude product was purified by column chromatography (mobile phase: hexane: EtOAc gradient). 0.18 g of the major isomer was obtained as a colorless oil (yield = 24.9%). 18 H 23 Calculated MS(ESI) mass for ClNO2 is 362.2; [M+H] + The m / z value of was 363.1. Step 2: Synthesis of HBS-061-192: Compound HBS-061-185 (0.177 g, 0.488 mmol) was dissolved in anhydrous dioxane (10 mL). 4.0 M HCl in dioxane (1.22 mL, 4.88 mmol) was added, and the reaction was vigorously stirred at 60° C. for 64 hours. LCMS showed complete conversion to the product (m / z value, 263). The reaction mixture was cooled to room temperature, filtered, and washed with hexane to give 0.16 g of a white solid (yield=97.7%). 13 H 15 Calculated MS(ESI) mass for ClN4 is 262.1; [M+H] + The m / z value of was 263.1. [ka] Step 1: Synthesis of HBS-061-176: Compound HBS-061-169 (0.704 g, 1.98 mmol) and pyrazole (0.427 g, 2.38 mmol) were dissolved in anhydrous dioxane (20 mL). CsCO (1.29 g, 3.96 mmol) was added, and the reaction mixture was heated to 100 °C with vigorous stirring. LCMS revealed high conversion to the product as a mixture of isomers (m / z value after 64 h: 363). The reaction mixture was cooled to room temperature, treated with water, and extracted with EtOAc. The EtOAc layer was dried over NaSO, filtered, and evaporated. The crude product was purified by column chromatography (mobile phase: hexane: EtOAc gradient). 0.64 g of the product was obtained as a colorless oil (yield = 89.3%). 18 H 23 Calculated MS(ESI) mass for ClNO2 is 362.2; [M+H] + The m / z value of was 363.1. Step 2: Synthesis of HBS-061-179: Compound HBS-061-176 (0.642 g, 1.77 mmol) was dissolved in anhydrous dioxane (20 mL). 4.0 M HCl in dioxane (2.21 mL, 8.84 mmol) was added, and the reaction was vigorously stirred at 60° C. for 18 hours. LCMS showed complete conversion to the product (m / z value, 263). The reaction mixture was cooled to room temperature, filtered, and washed with hexane to give 0.54 g of a powdery white solid (yield=91.6%). 13 H 15 Calculated MS(ESI) mass for ClN4 is 262.1; [M+H] + The m / z value of was 263.1. [ka] Step 1: Synthesis of HBS-066-001: HBS-061-169 (0.614 g, 1.73 mmol) and pyrazole (0.441 g, 2.07 mmol) were dissolved in anhydrous dioxane (20 mL). Cs2CO3 (1.12 g, 3.44 mmol) was added, and the reaction mixture was heated to 100 °C with vigorous stirring. LCMS revealed high conversion to the product as an 88:12 mixture of isomers (m / z value after 64 h, 397). The reaction mixture was cooled to room temperature, treated with water, and extracted with EtOAc. The EtOAc layer was dried over Na2SO4, filtered, and evaporated. The crude product was purified by column chromatography (mobile phase: hexane: EtOAc gradient). 0.51 g of the major isomer was obtained as a waxy white solid (yield = 74.9%). 19 H 23 Calculated MS(ESI) mass for F3N4O2 is 396.2; [M+H] + The m / z value of was 397.1. Step 2: Synthesis of HBS-066-005: Compound HBS-066-001 (0.513 g, 1.29 mmol) was dissolved in anhydrous dioxane (20 mL). 4.0 M HCl in dioxane (1.62 mL, 6.48 mmol) was added, and the reaction was vigorously stirred at 60° C. for 90 hours. LCMS showed complete conversion to the product (m / z value, 297). The reaction mixture was cooled to room temperature, filtered, and washed with hexane to give 0.36 g of a powdery white solid (yield=76.0%). 14 H 15 Calculated MS(ESI) mass for F3N4 is 296.1; [M+H] + The m / z value of was 297.1. [ka] Step 1: Synthesis of HBS-061-186: The carboxylic acid (1.720 g, 7.50 mmol) was dissolved in CHCl (40 mL). Hydroxylamidine (0.771 g, 5.00 mmol), HOBT (1.35 g, 10.0 mmol), EDC (1.917 g, 10.0 mmol), and TEA (3.50 mL, 25.0 mmol) were added sequentially and stirred at room temperature. LCMS revealed complete conversion to the acyl intermediate (m / z value, 366) after 24 h. The acyl intermediate was isolated by extractive workup with EtOAc and water to give a viscous yellow oil (2.44 g). This oil was dissolved in DCM (20 mL), toluene (30 mL) was added, and the reaction was heated to 100 °C in an open flask. LCMS revealed complete conversion of the product after 21 hours (m / z values: 348, 292, 248). Upon cooling, the reaction mixture was dissolved in EtOAc and extracted with a saturated aqueous solution of NaHCO3. The EtOAc layer was dried over Na2SO4, filtered, and evaporated. The crude product was purified by column chromatography (mobile phase: hexane: EtOAc gradient). 0.717 g of a colorless oil was obtained (yield = 41.0%). C 18 H 22 Calculated MS(ESI) mass for FN3O3 is 347.2; [M+H] + The m / z values ​​were 348.1, 292.0, and 248.0. Step 2: Synthesis of HBS-066-011 / HBS-066-022: Compound HBS-066-008 (0.717 g, 2.06 mmol) was dissolved in anhydrous dioxane (20 mL). 4.0 M HCl in dioxane (3.29 mL, 13.2 mmol) was added, and the reaction was vigorously stirred at 60° C. for 72 hours. LCMS showed complete conversion to the product (m / z value, 248). The reaction mixture was cooled to room temperature, filtered, and washed with hexane to give 0.53 g of a powdery white solid (yield=90.2%). 13 H 14 Calculated MS(ESI) mass for FNO is 247.1; [M+H] + The m / z value of was 248.1. [ka] Step 1: Synthesis of HBS-066-010: Compound HBS-061-169 (0.547 g, 1.54 mmol) and pyrazole (0.392 g, 1.85 mmol) were dissolved in anhydrous dioxane (20 mL). CsCO (1.00 g, 3.07 mmol) was added, and the reaction mixture was heated to 100 °C with vigorous stirring. LCMS revealed high conversion to the product (m / z value after 48 h: 396). The reaction mixture was cooled to room temperature, treated with water, and extracted with EtOAc. The EtOAc layer was dried over NaSO, filtered, and evaporated. The crude product was purified by column chromatography (mobile phase: hexane: EtOAc gradient). 0.47 g of the product was obtained as a colorless oil (yield = 77.7%). 20 H 24 Calculated MS(ESI) mass for F3N3O2 is 395.2; [M+H] + The m / z value of was 396.1. Step 2: Synthesis of HBS-066-013: Compound HBS-066-010 (0.473 g, 1.20 mmol) was dissolved in anhydrous dioxane (20 mL). 4.0 M HCl in dioxane (1.50 mL, 6.00 mmol) was added, and the reaction was vigorously stirred at 60° C. for 66 hours. LCMS showed complete conversion to the product (m / z value, 296). The reaction mixture was cooled to room temperature, filtered, and washed with hexane to give 0.37 g of a powdery white solid (yield=84.0%). 15 H 16 Calculated MS(ESI) mass for F3N3 is 295.1; [M+H] + The m / z value of was 296.1. [ka] Synthesis of HBS-066-019: HBS-061-169 (1.179 g, 3.32 mmol) was dissolved in anhydrous DMF (20 mL). NaN (0.323 g, 4.97 mmol) was added, and the reaction mixture was heated to 70 °C with vigorous stirring. LCMS revealed high conversion to the product (m / z values ​​after 24 h: 171, 127). The reaction mixture was cooled to room temperature, treated with water, and extracted with EtOAc. The EtOAc layer was washed with brine, dried over NaSO, filtered, and evaporated. The crude product was purified by column chromatography (mobile phase: hexane: EtOAc gradient). 0.630 g of product was obtained as a colorless oil (yield = 83.9%). 10 H 18 Calculated MS(ESI) mass for N4O2 is 226.2; [M+H] + The m / z values ​​were 171.1 and 127.1. [ka] Step 1: Synthesis of HBS066-017: Compound HBS-066-019 (0.177 g, 0.782 mmol) was dissolved in a mixture of toluene and t-BuOH (4:1 v / v mL). Acetylene (0.103 mL, 0.938 mmol), CuI (15 mg, 0.078 mmol), and DIPEA (0.272 mL, 1.56 mmol) were added sequentially. The reaction mixture was vigorously stirred at room temperature. LCMS revealed high conversion to the product (m / z value after 42 h, 329.0). The reaction mixture was evaporated, and the crude product was purified by column chromatography (mobile phase: hexane: EtOAc gradient). 0.159 g of the product was obtained as a white solid (yield = 62.0%). 18 H 24 Calculated MS(ESI) mass for N4O2 is 328.2; [M+H] + The m / z value of was 329.2. Step 2: Synthesis of HBS-066-021: Compound HBS-066-017 (0.159 g, 0.484 mmol) was dissolved in anhydrous dioxane (10 mL). 4.0 M HCl in dioxane (0.81 mL, 3.24 mmol) was added, and the reaction was stirred vigorously at 60° C. for 72 hours to form a suspension. LCMS showed complete conversion to the product (m / z value, 229). The reaction mixture was cooled to room temperature, filtered, and washed with hexanes. This sample was dissolved in MeOH, concentrated, and then dried in a vacuum oven to give 0.14 g of an off-white waxy solid (yield=95.3%). 13 H 16 Calculated MS(ESI) mass for N4 is 228.1; [M+H] + The m / z value of was 229.1. [ka] Step 1: Synthesis of HBS-066-024: Compound HBS066-019 (0.315 g, 1.39 mmol) was dissolved in a mixture of toluene and t-BuOH (6:1.5, v / v mL). Acetylene (0.200 g, 1.66 mmol), CuI (28 mg, 0.147 mmol), and DIPEA (0.485 mL, 2.78 mmol) were added sequentially. The reaction mixture was vigorously stirred at room temperature. LCMS revealed incomplete conversion to the product after 42 h. After 2.5 h, the mixture was heated to 60 °C to achieve a high conversion (m / z value, 347). The reaction mixture was evaporated, and the crude product was purified by column chromatography (mobile phase: hexane / EtOAc gradient). 0.32 g of the product was obtained as a white solid (yield = 66.6%). 18 H 23 Calculated MS(ESI) mass for FN4O2 is 346.2; [M+H] + The m / z value of was 347.1. Step 2: Synthesis of HBS-066-028: Compound HBS-066-024 (0.321 g, 0.927 mmol) was dissolved in anhydrous dioxane (20 mL). 4.0 M HCl in dioxane (2.32 mL, 9.27 mmol) was added, and the reaction was stirred vigorously at 60° C. for 42 hours. LCMS showed complete conversion to the product (m / z value, 247). The reaction mixture was cooled to room temperature, filtered, and washed with hexane to give a white waxy solid that adhered to the filter paper. This sample was dissolved in MeOH, concentrated, and then dried in a vacuum oven to give 0.32 g of a white waxy solid (yield). 13 H 15 The calculated MS(ESI) mass for FN4 is 246.1; [M+H] + The m / z value of was 247.1. [ka] Step 1: Synthesis of HBS-066-025: Compound HBS-066-019 (0.315 g, 1.39 mmol) was dissolved in a mixture of toluene and t-BuOH (6:1.5, v / v mL). Acetylene (0.228 g, 1.67 mmol), CuI (28 mg, 0.147 mmol), and DIPEA (0.485 mL, 2.78 mmol) were added sequentially. The reaction mixture was vigorously stirred at room temperature. LCMS revealed incomplete conversion after 42 h. After 2.5 h, the mixture was heated to 60 °C to achieve a high conversion (m / z value, 363). The reaction mixture was evaporated, and the crude product was purified by column chromatography (mobile phase: hexane: EtOAc gradient). 0.312 g of a white solid was obtained as product (yield = 61.8%). 18 H 23 Calculated MS(ESI) mass for ClNO2 is 362.2; [M+H] + The m / z value of was 363.1. Step 2: Synthesis of HBS-066-029: Compound HBS-066-025 (0.31 g, 0.860 mmol) was dissolved in anhydrous dioxane (20 mL). 4.0 M HCl in dioxane (2.15 mL, 8.60 mmol) was added, and the reaction was stirred vigorously at 60° C. for 42 hours to form a suspension. LCMS showed complete conversion to the product (m / z value, 263). The reaction mixture was cooled to room temperature, filtered, and washed with hexane to give 0.260 g of a white solid (yield=90.1%). 13 H 15 Calculated MS(ESI) mass for ClN4 is 262.1; [M+H] + The m / z value of was 263.1. [ka] Step 1: Synthesis of HBS-066-032: HBS-061-169 (1.01 g, 2.83 mmol) and pyrazole (0.607 g, 3.40 mmol) were dissolved in anhydrous dioxane (25 mL). CsCO (1.85 g, 5.68 mmol) was added, and the reaction mixture was heated to 100 °C with vigorous stirring. LCMS revealed high conversion to the product as a 92:8 mixture of isomers (m / z value after 24 h, 362). The reaction mixture was cooled to room temperature, treated with water, and extracted with EtOAc. The EtOAc layer was dried over NaSO, filtered, and evaporated. The crude product was purified by column chromatography (mobile phase: hexane: EtOAc gradient). 0.518 g of the major isomer was obtained as a colorless oil (yield = 50.5%). 19 H 24 Calculated MS(ESI) mass for ClN3O2 is 361.2; [M+H] + The m / z value of was 362.1. Step 2: Synthesis of HBS-066-035 / HBS-066-044: Compound HBS-066-032 (0.518 g, 1.43 mmol) was dissolved in anhydrous dioxane (30 mL). 4.0 M HCl in dioxane (3.58 mL, 14.3 mmol) was added, and the reaction was stirred vigorously at 60° C. for 66 hours to form a suspension. LCMS showed complete conversion to the product (m / z value, 262). The reaction mixture was cooled to room temperature, filtered, and washed with hexane to give 0.395 g of a powdery white solid (yield=82.4%). 14 H 16 Calculated MS(ESI) mass for ClN3 is 261.1; [M+H] + The m / z value of was 262.1. [ka] Step 1: Synthesis of HBS066-034: HBS-061-169 (0.499 g, 1.40 mmol) and pyrazole (0.243 g, 1.68 mmol) were dissolved in anhydrous dioxane (12 mL). Cs2CO3 (0.915 g, 2.81 mmol) was added, and the reaction mixture was heated to 100 °C with vigorous stirring. LCMS revealed high conversion to the product as a mixture of isomers (m / z value after 90 h: 328). The reaction mixture was cooled to room temperature, treated with water, and extracted with EtOAc. The EtOAc layer was dried over Na2SO4, filtered, and evaporated. TLC (95:5, DCM, MeOH) showed separation of the isomers. The crude product was purified by column chromatography (mobile phase: DCM:MeOH gradient). 0.253 g of the major isomer was obtained as a yellow oil (yield = 55.0%). 19 H 25 Calculated MS(ESI) mass for N3O2 is 327.2; [M+H] + The m / z value of was 328.2. Step 2: Synthesis of HBS-066-039: Compound HBS-066-034 (0.253 g, 7.73 mmol) was dissolved in anhydrous dioxane (20 mL). 4.0 M HCl in dioxane (1.93 mL, 4.88 mmol) was added, and the reaction was stirred vigorously at 60° C. for 27 hours to form a suspension. LCMS showed complete conversion to the product (m / z value, 228). The reaction mixture was cooled to room temperature, filtered, and washed with hexanes. This sample was dissolved in MeOH, concentrated, and then dried in a vacuum oven to give 0.168 g of a white crystalline wax (yield=72.4%). 14 H 17 Calculated MS(ESI) mass for N3 is 227.1; [M+H] + The m / z value of was 228.1. [ka] Step 1: Synthesis of HBS-066-036: Compound HBS-061-169 (0.978 g, 2.75 mmol) and pyrazole (0.545 g, 3.02 mmol) were dissolved in anhydrous dioxane (25 mL). CsCO (1.79 g, 5.49 mmol) was added, and the reaction mixture was heated to 100 °C with vigorous stirring. LCMS revealed high conversion to the product as a 96:4 mixture of isomers (m / z value after 64 h, 364). The reaction mixture was cooled to room temperature, treated with water, and extracted with EtOAc. The EtOAc layer was dried over NaSO, filtered, and evaporated. The crude product was purified by column chromatography (mobile phase: hexane: EtOAc gradient). 0.682 g of the major isomer was obtained as a colorless oil (yield = 68.2%). 19 H 23 Calculated MS(ESI) mass for F2N3O2 is 363.2; [M+H] + The m / z value of was 364.2. Step 2: Synthesis of HBS-066-042: Compound HBS-066-036 (0.682 g, 1.88 mmol) was dissolved in anhydrous dioxane (20 mL). 4.0 M HCl in dioxane (2.35 mL, 9.40 mmol) was added, and the reaction was stirred vigorously at 60° C. for 66 hours to form a suspension. LCMS showed complete conversion to the product (m / z value, 264). The reaction mixture was cooled to room temperature, filtered, and washed with hexane to give a film that adhered to the filter paper. This sample was dissolved in MeOH, concentrated, and then dried in a vacuum oven to give 0.55 g of an off-white wax (yield=87.2%). 14 H 15 Calculated MS(ESI) mass for F2N3 is 263.1; [M+H] + The m / z value of was 264.2. [ka] Step 1: Synthesis of HBS-066-037: Compound HBS-061-169 (0.963 g, 2.71 mmol) and pyrazole (0.532 g, 2.98 mmol) were dissolved in anhydrous dioxane (25 mL). Cs2CO3 (1.76 g, 5.40 mmol) was added, and the reaction mixture was heated to 100 °C with vigorous stirring. LCMS revealed high conversion to the product (m / z value after 64 h: 362). The reaction mixture was cooled to room temperature, treated with water, and extracted with EtOAc. The EtOAc layer was dried over Na2SO4, filtered, and evaporated. The crude product was purified by column chromatography (mobile phase: hexane: EtOAc gradient). 0.65 g of the major isomer was obtained as a yellow oil (yield = 66.4%). C 19 H 24 Calculated MS(ESI) mass for ClN3O2 is 361.2; [M+H] + The m / z value of was 362.1. Step 2: Synthesis of HBS-066-043: Compound HBS066-037 (0.651 g, 1.80 mmol) was dissolved in anhydrous dioxane (20 mL). 4.0 M HCl in dioxane (2.25 mL, 9.00 mmol) was added, and the reaction was stirred vigorously at 60° C. for 66 hours to form a suspension. LCMS showed complete conversion to the product (m / z value, 262). The reaction mixture was cooled to room temperature, filtered, and washed with hexane to give a film that adhered to the filter paper. This sample was dissolved in MeOH, concentrated, and then dried in a vacuum oven to give 0.54 g of a beige wax (yield=88.9%). 14 H 16 Calculated MS(ESI) mass for ClN3 is 261.1; [M+H] + The m / z value of was 262.1. [ka] Step 1: Synthesis of HBS-066-046: Compound HBS-061-169 (1.355 g, 3.81 mmol) and pyrazole (0.680 g, 4.19 mmol) were dissolved in anhydrous dioxane (40 mL). CsCO (2.48 g, 7.61 mmol) was added, and the reaction mixture was heated to 100 °C with vigorous stirring. LCMS revealed high conversion to the product (m / z value after 48 h: 346). The reaction mixture was cooled to room temperature, treated with water, and extracted with EtOAc. The EtOAc layer was dried over NaSO, filtered, and evaporated. TLC (95:5, DCM, MeOH) showed separation of the isomers. The crude product was purified by column chromatography (mobile phase: DCM:MeOH gradient). 0.63 g of the major isomer was obtained as a yellow oil (yield = 47.9%). 19 H 24 Calculated MS(ESI) mass for FN3O2 is 345.2; [M+H] + The m / z value of was 346.2. Step 2: Synthesis of HBS-066-050: Compound HBS-066-046 (0.61 g, 1.78 mmol) was dissolved in anhydrous dioxane (20 mL). 4.0 M HCl in dioxane (2.22 mL, 8.88 mmol) was added, and the reaction was stirred vigorously at 60° C. for 68 hours to form a suspension. LCMS showed complete conversion to the product (m / z value, 246). The reaction mixture was cooled to room temperature, filtered, and washed with hexane to give 0.478 g of a white solid (yield=84.5%). 14 H 16 The calculated MS(ESI) mass for FN3 is 245.1; [M+H] + The m / z value of was 246.2. [ka] Step 1: Synthesis of HBS-066-047: Compound HBS-061-169 (0.858 g, 2.41 mmol) and pyrazole (0.564 g, 2.66 mmol) were dissolved in anhydrous dioxane (25 mL). CsCO (1.57 g, 4.82 mmol) was added, and the reaction mixture was heated to 100 °C with vigorous stirring. LCMS revealed high conversion to the product as a 92:8 mixture of isomers (m / z value after 64 h, 396). The reaction mixture was cooled to room temperature, treated with water, and extracted with EtOAc. The EtOAc layer was dried over NaSO, filtered, and evaporated. The crude product was purified by column chromatography (mobile phase: hexanes / EtOAc gradient). 0.70 g of the major isomer was obtained as a colorless oil (yield = 73.8%). 20 H 24 Calculated MS(ESI) mass for F3N3O2 is 395.2; [M+H] + The m / z value of was 396.2. Step 2: Synthesis of HBS-066-053: Compound HBS-066-047 (0.704 g, 1.78 mmol) was dissolved in anhydrous dioxane (20 mL). 4.0 M HCl in dioxane (2.20 mL, 8.80 mmol) was added, and the reaction was stirred vigorously at 60° C. for 72 hours. LCMS showed complete conversion to the product (m / z value, 296). The reaction mixture was cooled to room temperature, filtered, and washed with hexanes. This sample was dissolved in MeOH, concentrated, and then dried in a vacuum oven to give 0.59 g of an off-white, firm solid (yield=90.1%). 15 H 16 Calculated MS(ESI) mass for F3N3 is 295.1; [M+H] + The m / z value of was 296.2. [ka] Step 1: Synthesis of HBS-066-048: HBS061-169 (0.866 g, 2.44 mmol) and pyrazole (0.495 g, 2.68 mmol) were dissolved in anhydrous dioxane (25 mL). Cs2CO3 (1.59 g, 4.88 mmol) was added, and the reaction mixture was heated to 100 °C with vigorous stirring. LCMS revealed high conversion to the product as a mixture of isomers (m / z value after 64 h, 368). The reaction mixture was cooled to room temperature, treated with water, and extracted with EtOAc. The EtOAc layer was dried over Na2SO4, filtered, and evaporated. TLC (2:1, hexane:EtOAc) showed separation of the isomers. The crude product was purified by column chromatography (mobile phase: hexane:EtOAc gradient). 0.670 g of the major isomer was obtained as a colorless oil (yield = 74.7%). 17 H 22 Calculated MS(ESI) mass for ClN3O2S is 367.1; [M+H] + The m / z value of was 368.1. Step 2: Synthesis of HBS-066-054: Compound HBS-066-048 (0.670 g, 1.82 mmol) was dissolved in anhydrous dioxane (20 mL). 4.0 M HCl in dioxane (2.30 mL, 9.20 mmol) was added, and the reaction was stirred vigorously at 60° C. for 72 hours. LCMS showed complete conversion to the product (m / z value, 268). The reaction mixture was cooled to room temperature, filtered, and washed with hexane to give a hard solid that adhered to the filter paper. This sample was dissolved in MeOH, concentrated, and then dried in a vacuum oven to give 0.53 g of an off-white hard solid (yield=85.9%). 12 H 14 Calculated MS(ESI) mass for ClN3S is 267.1; [M+H] + The m / z value of was 268.1. [ka] Step 1: Synthesis of HBS-037-067: 2-Chloro-5-trifluoromethylpyridine (0.33 g, 1.82 mmol) and (S)-1-Boc-2-(aminomethyl)-pyrrolidine (0.36 g, 1.81 mmol) were dissolved in dry DMSO (5.0 mL). DIPEA (1.6 mL, 9.1 mmol) was added, and the rxn mixture was stirred at 100 °C for 4 hours. TLC showed product formation. The rxn mixture was diluted with water. The product was extracted with ethyl acetate. The combined ethyl acetate layers were washed with water and then brine. The organic layer was separated and dried over anhydrous sodium sulfate. The crude product was obtained by evaporating the solvent. The crude product was purified using an ISCO combi-flash chromatography system (mobile phase: EtOAc:hexane gradient). 0.24 g of the desired liquid product was isolated (39.0% yield). C 16 H 22 Calculated MS(ESI) mass for F3N3O2 is 345.0; [M+H] + The m / z value of was 346.1. Step 2: Synthesis of HBS-037-069: HBS-037-067 (0.24 g, 0.71 mmol) was dissolved in dry dioxane (3.0 mL). 4.0 M HCl solution in dioxane (1.77 mL, 7.08 mmol) was added, and the rxn mixture was stirred at 50° C. for 4 hours. LCMS showed product formation (m / z value, 246). The rxn mixture was concentrated under reduced pressure to give a solid product (0.19 g, 78.4% yield). 11 H 14 Calculated MS(ESI) mass for F3N3 is 245.2; [M+H] + The m / z value of was 246.0; 1 H NMR (400MHz, chloroform-d) δ ppm 1.76 - 2.01 (m, 1 H) 2.01 - 2.15 (m, 1 H) 2.15 - 2.28 (m, 1 H) 2.36 (br s, 1 H) 3.25 - 3.46 (br s, 1 H) 3.48 (br s, 1 H) 4.04 (br s, 2 H) 4.31 (br s, 1 H) 7.47 (br s, 1 H) 7.86 (br s, 1 H) 8.19 (br s, 1 H) 9.41 - 10.42 (br s, 1 H). [ka] Step 1: Synthesis of HBS-037-070: 2-Chloro-5-ethyl-pyrimidine (0.2 g, 1.37 mmol) and (S)-1-Boc-2-(aminomethyl)-pyrrolidine (0.28 g, 1.37 mmol) were dissolved in dry DMF (5.0 mL). Cs2CO3 (0.89 g, 2.75 mmol) was added, and the rxn mixture was stirred at 120 °C for 24 hours. TLC showed product formation. The rxn mixture was diluted with water. The product was extracted with ethyl acetate. The combined ethyl acetate layers were washed with water and then brine. The organic layer was separated and dried over anhydrous sodium sulfate. The crude product was obtained by evaporating the solvent. The crude product was purified using an ISCO combi-flash chromatography system (mobile phase: EtOAc:hexane gradient). 0.27 g of the desired liquid product was isolated (64.2% yield). C 16 H26 Calculated MS(ESI) mass for N4O2 is 306.4; [M+H] + The m / z value of was 307.1. Step 2: Synthesis of HBS-037-074: HBS-037-070 (0.27 g, 0.88 mmol) was dissolved in dry dioxane (3.0 mL). 4.0 M HCl solution in dioxane (2.2 mL, 8.81 mmol) was added, and the rxn mixture was stirred at 60° C. for 4 hours. LCMS showed product formation (m / z value, 207). The rxn mixture was concentrated under reduced pressure to give a solid product (0.31 g, yield). 11 H 18 Calculated MS(ESI) mass for N4 is 206.3; [M+H] + The m / z value of was 207.1. [ka] Step 1: Synthesis of HBS-037-095: [(2S,3R)-1-[4-methoxyphenyl)methyl]-3-methylpiperidin-2-yl]methanamine (0.35 g, 1.4 mmol) and 2-chloro-5-ethyl-pyrimidine (0.2 g, 1.4 mmol) were dissolved in dry DMF (4.0 mL). K2CO3 (0.39 g, 2.82 mmol) was added, and the rxn mixture was stirred at 120 °C for 6 hours. TLC showed product formation. The rxn mixture was diluted with water. The product was extracted with ethyl acetate. The combined ethyl acetate layers were washed with water and then brine. The organic layer was separated and dried over anhydrous sodium sulfate. The crude product was obtained by evaporating the solvent. The crude product was purified using an ISCO combi-flash chromatography system (mobile phase: EtOAc:hexane gradient). 0.33 g of product was obtained (65.4% yield). C 21 H 30 Calculated MS(ESI) mass for NO is 354.5; [M+H] + The m / z value of was 355.2; 1H NMR (400MHz, chloroform-d) δ ppm 0.85 - 0.94 (d, J= 8.0 Hz, 3 H) 1.16 (t, J= 8.0 Hz, 3 H) 1.25 - 1.47 (m, 2 H) 1.50 - 1.84 (m, 2 H) 2.05 - 2.25 (m, 1 H) 2.35 - 2.47 (q, J= 8.0 Hz, 2 H) 2.47 - 2.60 (m, 1 H) 2.62 - 2.83 (m, 2 H) 3.33 - 3.46 (m, 2 H) 3.77 (s, 3 H) 3.78 - 3.85 (m, 2 H) 5.68 (br s, 1 H) 6.84 (d, J= 8.66 Hz, 2H) 7.24 - 7.31 (m, 2H) 8.12 (s, 2H). Step 2: Synthesis of HBS-037-101: HBS-037-095 (0.1 g, 0.3 mmol) was dissolved in MeOH (3.0 mL). 20.0% Pd-OH / C (30.0 mg) was added, and the rxn mixture was stirred at ambient temperature for 24 hours. TLC revealed that only a small amount of starting material was present, and product formation had occurred. Additional 20.0% Pd-OH / C (30.0 mg) was added, and the rxn mixture was stirred at ambient temperature for another 24 hours. TLC indicated completion of the rxn. LCMS data indicated product formation (m / z value, 235). The rxn mixture was filtered through Celite and washed with MeOH. The filtrate was evaporated under reduced pressure to give 66.0 mg of crude product. This crude product was used in the next step without purification. 13 H 22 Calculated MS(ESI) mass for N4 is 234.3; [M+H] + The m / z value of was 235.2. [ka] Step 1: Synthesis of HBS-037-106: [(2S,3R)-1-[4-methoxyphenyl)methyl]-3-methylpiperidin-2-yl]methanamine (0.32 g, 1.29 mmol) and 2-chloro-5-trifluoromethylpyridine (0.23 g, 1.29 mmol) were dissolved in dry DMF (5.0 mL). KCO (0.36 g, 2.58 mmol) was added, and the rxn mixture was stirred at 120 °C for 4 hours. TLC showed product formation, and LCMS showed product formation (m / z value, 394). The rxn mixture was diluted with water. The product was extracted with ethyl acetate. The combined ethyl acetate layers were washed with water and then brine. The organic layer was separated and dried over anhydrous sodium sulfate. The crude product was obtained by evaporating the solvent. The crude product was purified using an ISCO combi-flash chromatography system (mobile phase: DCM:MeOH (90:10 v / v mL)). The product band was isolated. 0.41 g of pure product (m / z value, 394) was obtained (yield 81.4%). 21 H 26 The calculated MS(ESI) mass for F3N3O was 393.5; the m / z value for M+H]+ was 394.1; 1 H NMR (400MHz, chloroform-d) δ ppm 0.88 (d, J= 7.04 Hz, 3 H) 1.19 - 1.46 (m, 2 H) 1.54 - 1.65 (m, 1 H) 1.65 - 1.83 (m, 1 H) 2.07 - 2.22 (m, 1 H) 2.50 - 2.65 (m, 1 H) 2.65 - 2.80 (m, 2 H) 3.20 - 3.38 (m, 2 H) 3.78 (s, 3 H) 3.79 - 3.84 (m, 2 H) 5.67 (br s, 1 H) 6.32 (d, J= 8.80 Hz, 1 H) 6.80 - 6.89 (m, 2H) 7.15 - 7.29 (m, 2 H) 7.49 (dd, J= 8.80, 2.35 Hz, 1 H) 8.28 - 8.32 (m, 1 H). Step 2: Synthesis of HBS-037-110: HBS-037-106 (0.02 g, 0.5 mmol) was dissolved in MeOH (5.0 mL). Under a hydrogen gas atmosphere, 10.0% Pd / C (60.0 mg) was added, and the rxn mixture was stirred at ambient temperature for 24 hours. TLC showed the completion of the rxn. LCMS data showed product formation (m / z value, 274). The rxn mixture was filtered through Celite and washed with MeOH. The filtrate was evaporated under reduced pressure to give 0.16 g of crude product. C 13 H 18 Calculated MS(ESI) mass for F3N3 is 273.3; [M+H] + The m / z value of was 274.1. [ka] Step 1: Synthesis of HBS-037-152: N-Boc-L-prolinol (0.2 g, 0.99 mmol) was dissolved in dry DMF (4.0 mL). NaH (0.08 g, 2.0 mmol) was added under ice cooling. 2-Chloro-5-ethyl-pyrimidine (0.2 g, 1.5 mmol) was added under cooling, and the rxn mixture was gradually warmed to room temperature with stirring for 3 hours. LCMS showed the formation of the product (m / z value, 308.2). The rxn mixture was diluted with water. The product was extracted three times with ethyl acetate. The EtOAc layer was separated and dried over anhydrous Na2SO4. The crude product was obtained by evaporating the solvent. The crude product was purified by column chromatography (mobile phase: EtOAc:hexane gradient). (Yield) 0.3 g of pure product was obtained. C 16 H 25 Calculated MS(ESI) mass for N3O3 is 307.4; [M+H] + The m / z value of was 308.2. Step 2: Synthesis of HBS-037-154: HBS-037-152 (0.3 g, 0.99 mmol) was dissolved in dry dioxane (4.0 mL). 4.0 M HCl solution in dioxane (2.48 mL, 9.9 mmol) was added, and the rxn mixture was stirred at 60° C. for 4 hours. LCMS showed product formation (m / z value, 208.1). The rxn mixture was concentrated under reduced pressure to give 0.32 g of liquid product. 11 H 17Calculated MS(ESI) mass for NO is 207.3; [M+H] + The m / z value of was 208.1. [ka] Step 1: Synthesis of HBS-037-153: N-Boc-L-prolinol (0.2 g, 0.99 mmol) was dissolved in dry DMF (4.0 mL). NaH (0.08 g, 2.0 mmol) was added, followed by 2-chloro-5-trifluoromethylpyridine (0.27 g, 1.5 mmol). The rxn mixture was heated at 70 °C for 3 hours. LCMS showed product formation (m / z value, 347.1). The rxn mixture was diluted with water. The product was extracted three times with ethyl acetate. The EtOAc layer was separated and dried over anhydrous Na2SO4. The crude product was obtained by evaporating the solvent. The crude product was purified by column chromatography (mobile phase: EtOAc:hexane gradient). 0.3 g of pure product was obtained (86.0% yield). C 16 H 21 Calculated MS(ESI) mass for F3N2O3 is 346.3; [M+H] + The m / z value of was 347.1. Step 1: Synthesis of HBS-037-155: HBS-037-153 (0.3 g, 0.86 mmol) was dissolved in dry dioxane (2.0 mL). 4.0 M HCl solution in dioxane (2.14 mL, 8.6 mmol) was added, and the rxn mixture was stirred at 60 °C for 4 hours. LCMS showed product formation (m / z value, 247.1). The rxn mixture was filtered and washed with hexane (5.0 mL x 3) to give 0.27 g of solid product (yield). 11 H 13 Calculated MS(ESI) mass for FNO is 246.2; [M+H] + The m / z value of was 247.1; 1H NMR (400MHz, Chloroform-d) δ ppm 1.87 - 1.99 (m, 1 H) 1.99 - 2.08 (m, 1 H) 2.08 - 2.17 (m, 1 H) 2.17 - 2.29 (m, 1 H) 3.32 - 3.49 (m, 2 H) 3.96 - 4.09 (m, 1 H) 4.60 - 4.77 (m, 2 H) 7.00 (d, J= 8.73 Hz, 1 H) 7.77 (dd, J= 8.73, 2.35 Hz, 1 H) 8.37 - 8.42 (m, 1 H) 9.74 (br s, 1 H) 10.32 (br s, 1 H). [ka] JPEG2025530768000106.jpg61158 Step 1: Synthesis of HBS-039-033: N-Boc-L-prolinol (0.5 g, 2.48 mmol) was dissolved in DCM (10.0 mL). DIPEA (0.9 mL, 4.97 mmol) was added, followed by DMAP (0.61 g, 4.97 mmol). The rxn mixture was cooled in an ice bath, and p-TsCl (0.52 g, 2.73 mmol) was added. The rxn mixture was stirred and allowed to warm gradually to room temperature for 16 hours. LCMS showed product formation (m / z values, 256, 300). The rxn mixture was diluted with water. The product was extracted with DCM. The DCM layer was separated and dried over anhydrous Na2SO4. Evaporation of the solvent gave 0.88 g of product (yield). C 17 H 25 Calculated MS(ESI) mass for NO5S is 355.5; [M+H] + The m / z values ​​were 300.1 and 256.1. Step 2: Synthesis of HBS-039-034: HBS-039-033 (0.88 g, 2.48 mmol) and 3-phenyl-1H-pyrazole (0.43 g, 2.98 mmol) were dissolved in dry DMF (5.0 mL). Cs2CO3 (1.61 g, 4.96 mmol) was added, and the rxn mixture was stirred at 70 °C for 4 hours. LCMS showed product formation (m / z value, 328). The rxn mixture was cooled to ambient temperature and diluted with water. The product was extracted with ethyl acetate. The EtOAc layer was separated and dried over anhydrous Na2SO4. The crude product was obtained by evaporating the solvent. The crude product was purified by column chromatography (mobile phase: EtOAc:hexane gradient). 0.73 g of pure product was obtained (89.5% yield). C 19 H 25 Calculated MS(ESI) mass for N3O2 is 327.4; [M+H] + The m / z value of was 328.3. Step 3: Synthesis of HBS-039-036: HBS-039-034 (0.73 g, 2.24 mmol) was dissolved in dry dioxane (10.0 mL). 4.0 M HCl solution in dioxane (2.8 mL, 11.2 mmol) was added, and the rxn mixture was stirred at 50° C. for 16 hours. LCMS showed product formation (m / z value, 228). The rxn mixture was filtered and washed with hexane (5.0 mL×3) to give 0.53 g of solid product (yield). 14 H 17 Calculated MS(ESI) mass for N3 is 227.1; [M+H] + The m / z value of was 228.2; 1H NMR (400MHz, Chloroform-d) δ ppm 1.74 - 1.94 (m, 1 H) 1.94 - 2.05 (m, 1 H) 2.06 - 2.15 (m, 1 H) 2.16 - 2.35 (m, 1 H) 3.21 - 3.45 (m, 2 H) 4.33 (br s, 1 H) 4.86 (dd, J=14.82, 3.96 Hz, 1 H) 5.07 (br dd, J=14.67, 8.66 Hz, 1 H) 6.75 (d, J= 2.20 Hz, 1 H) 7.34 - 7.48 (m, 3 H) 7.76 - 7.87 (m, 2 H) 8.44 (d, J= 2.49Hz, 1H) 9.51 - 10.12 (br, 1 H). [ka] Step 1: Synthesis of HBS-039-118: (S)-1-Boc-2-(aminomethyl)pyrrolidine (1.5 g, 5.6 mmol) and 2-chloro-5-fluoropyridine (0.033 g, 0.25 mmol) were dissolved in dioxane (3.0 mL). Anhydrous t-BuOK (0.042 g, 0.37 mmol) was added, followed by Pd2(dba)3 (0.023 g, 0.025 mmol) and X-Phos (0.012 g, 0.025 mmol). Under a nitrogen atmosphere, the rxn mixture was stirred at 110 °C for 4 hours. LCMS data indicated product formation (m / z value, 296.0). The rxn mixture was filtered through a celite bed and washed with ethyl acetate. The filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified using an ISCO combi-flash chromatography system (mobile phase: EtOAc:hexane gradient). 0.032 g of product was obtained (86.8% yield). 15 H 22 Calculated MS(ESI) mass for FN3O2 is 295.35; [M+H] + The m / z value of was 296.0. Step 2: Synthesis of HBS-039-120: Compound HBS-039-118 (0.032 g, 0.11 mmol) was dissolved in dry dioxane (1.0 mL). 4.0 M HCl solution in dioxane (0.27 mL, 1.1 mmol) was added, and the rxn mixture was stirred at ambient temperature for 16 hours. LCMS showed product formation (m / z value, 196.1). The rxn mixture was concentrated under reduced pressure to give 0.033 g of product (yield). 10 H 14 The calculated MS(ESI) mass for FN3 is 195.24; [M+H] + The m / z value of was 196.1. [ka] Step 1: Synthesis of HBS-039-131: N-Boc-L-prolinol (0.2 g, 0.99 mmol) was dissolved in dry DMF (2.0 mL). NaH (0.12 g, 2.98 mmol) was added at 0 °C. The rxn mixture was stirred at 0 °C for 30 minutes. 2-Bromo-5-fluoro-pyridine (0.26 g, 1.49 mmol) in DMF (1.0 mL) was added at 0 °C. The rxn mixture was gradually warmed to ambient temperature and then heated at 70 °C for 3 hours. LCMS showed the formation of the product (m / z value, 357.1). The rxn mixture was cooled to ambient temperature and diluted with water. The product was extracted with ethyl acetate. The EtOAc layer was separated and dried over anhydrous NaSO. The crude product was obtained by evaporating the solvent. The crude product was purified by column chromatography (mobile phase: EtOAc:hexane gradient). 0.25 g of product was obtained (yield 70.4%). 15 H 21 Calculated MS(ESI) mass for BrN2O3 is 357.24; [M+H] + The m / z value of was 357.1. Step 2: Synthesis of HBS-039-137: Compound HBS-039-131 (0.25 g, 0.7 mmol) was dissolved in dry dioxane (5.0 mL). 4.0 M HCl solution in dioxane (1.74 mL, 7.0 mmol) was added, and the rxn mixture was stirred at 50° C. for 6 hours. LCMS showed product formation (m / z value, 257). The rxn mixture was filtered and dried to give 0.2 g of product (86.6% yield). 10 H 13 Calculated MS(ESI) mass for BrNO is 257.13; [M+H] + The m / z value of was 257.0. [ka] Step 1: Synthesis of HBS-039-144: (S)-1-Boc-2-(hydroxymethyl)piperidine (0.25 g, 1.16 mmol) was dissolved in anhydrous DMF (5.0 mL). NaH (0.14 g, 3.48 mmol) was added at 0 °C, and the reaction mixture was stirred for 15 minutes. 2-Chloro-5-trifluoromethylpyridine (0.32 g, 1.74 mmol) was added, and the reaction mixture was gradually warmed to ambient temperature. The reaction mixture was heated at 80 °C for 8 hours. LCMS showed the formation of the product (m / z value, 361.2). The rxn mixture was cooled to ambient temperature and diluted with water. The product was extracted with ethyl acetate. The EtOAc layer was separated and dried over anhydrous Na2SO4. The crude product was obtained by evaporation of the solvent. The crude product was purified by column chromatography (mobile phase: EtOAc:hexane gradient). 0.2 g of product was obtained (yield 48.0%). 17 H 23 Calculated MS(ESI) mass for F3N2O3 is 360.37; [M+H] + The m / z value of was 361.2. Step 2: Synthesis of HBS-039-160: Compound HBS-039-144 (0.2 g, 0.56 mmol) was dissolved in anhydrous dioxane (5.0 mL). 4.0 M HCl in dioxane (1.39 mL, 5.58 mmol) was added, and the reaction mixture was heated at 50° C. for 3 hours. LCMS showed product formation (m / z value, 261.1). The reaction mixture was concentrated under reduced pressure to give 0.16 product (86.1% yield). 12 H 15 Calculated MS(ESI) mass for FNO is 260.26; [M+H] + The m / z value of was 261.1. [ka] Step 1: Synthesis of HBS-039-166: N-Boc-L-prolinol (1.0 g, 4.97 mmol) was dissolved in DCM (15.0 mL). DIPEA (1.72 mL, 9.94 mmol) was added, followed by DMAP (1.21 g, 9.94 mmol). The rxn mixture was cooled to 0°C in an ice bath. p-TsCl (1.04 g, 5.46 mmol) was added. The rxn mixture was stirred and allowed to warm gradually to room temperature for 16 hours. LCMS showed product formation (m / z value, 256). The reaction mixture was diluted with water. The product was extracted with DCM. The DCM layer was separated and dried over anhydrous Na2SO4. The solvent was evaporated to give 1.76 g of product (yield). C 17 H 25 Calculated MS(ESI) mass for NO5S is 355.45; [M-Boc] + The m / z value of was 256.0. Step 2: Synthesis of HBS-039-172: Compound HBS-039-166 (0.84 g, 2.36 mmol) and 3-[4-(trifluoromethyl)phenyl]-1H-pyrazole (0.5 g, 2.36 mmol) were dissolved in dry DMF (10.0 mL). Anhydrous Cs2CO3 (1.53 g, 4.71 mmol) was added, and the rxn mixture was stirred at 70 °C for 12 hours. LCMS showed product formation (m / z value, 396.3). The rxn mixture was cooled to ambient temperature and diluted with water. The product was extracted with ethyl acetate. The combined EtOAc layers were separated and dried over anhydrous Na2SO4. The crude product was obtained by evaporating the solvent. The crude product was purified by column chromatography (mobile phase: EtOAc:hexane gradient). 0.8 g of pure product was obtained (85.9% yield). C 20 H 24 Calculated MS(ESI) mass for F3N3O2 is 395.42; [M+H] + The m / z value of was 396.3. Step 3: Synthesis of HBS-039-176: Compound HBS-039-172 (0.8 g, 2.02 mmol) was dissolved in dry dioxane (20.0 mL). 2.0 M HCl solution in diethyl ether (4.1 mL, 8.1 mmol) was added, and the rxn mixture was stirred at 60° C. for 16 hours. LCMS showed product formation (m / z value, 296.1). The rxn mixture was cooled, and the precipitate was filtered. The precipitate was dried to give 0.6 g of solid product (89.4% yield). C 14 H 17 Calculated MS(ESI) mass for N3 is 227.1; [M+H] + The m / z value of was 228.2. [ka] Step 1: Synthesis of HBS-039-177: N-Boc-L-prolinol (1.0 g, 4.97 mmol) was dissolved in DCM (15.0 mL). DIPEA (1.72 mL, 9.94 mmol) was added, followed by DMAP (1.21 g, 9.94 mmol). The rxn mixture was cooled to 0°C in an ice bath. p-TsCl (1.04 g, 5.46 mmol) was added. The rxn mixture was stirred and allowed to warm to room temperature gradually over 16 hours. LCMS showed product formation (m / z values, 256.1, 300.1). The reaction mixture was diluted with water. The product was extracted with DCM. The DCM layer was separated and dried over anhydrous Na2SO4. Evaporation of the solvent gave 1.76 g of product (yield). C 17 H 25 Calculated MS(ESI) mass for NO5S is 355.45; [M-Boc] + The m / z values ​​were 256.1 and 300.1. Step 2: Synthesis of HBS-039-178: Compound HBS-039-177 (1.0 g, 6.17 mmol) and 3-[4-fluorophenyl]-1H-pyrazole (1.0 g, 6.17 mmol) were dissolved in dry DMF (20.0 mL). Anhydrous Cs2CO3 (4.0 g, 12.33 mmol) was added, and the rxn mixture was stirred at 70 °C for 12 hours. LCMS showed product formation (m / z value, 346.3). The rxn mixture was cooled to ambient temperature and diluted with water. The product was extracted with ethyl acetate. The combined EtOAc layers were separated and dried over anhydrous Na2SO4. The crude product was obtained by evaporating the solvent. The crude product was purified by column chromatography (mobile phase: EtOAc:hexane gradient). 2.0 g of pure product was obtained (yield 93.9%). C 19 H 24 Calculated MS(ESI) mass for FN3O2 is 345.41; [M+H] + The m / z value of was 346.3. Step 3: Synthesis of HBS-039-179: Compound HBS-039-178 (2.0 g, 5.79 mmol) was dissolved in dry dioxane (20.0 mL). 2.0 M HCl solution in diethyl ether (11.58 mL, 23.16 mmol) was added, and the rxn mixture was stirred at 60° C. for 16 hours. LCMS showed product formation (m / z value, 24621). The rxn mixture was cooled, and the precipitate was filtered. The precipitate was dried to give 1.63 g of solid product (yield). C 14 H 16 The calculated MS(ESI) mass for FN3 is 245.3; [M+H] + The m / z value of was 246.2. [ka] Step 1: Synthesis of HBS-055-090: N-Boc-L-prolinol (0.5 g, 2.48 mmol) was dissolved in DCM (10.0 mL). DIPEA (0.9 mL, 4.97 mmol) was added, followed by DMAP (0.61 g, 4.97 mmol). The rxn mixture was cooled to 0°C in an ice bath. p-TsCl (0.52 g, 2.73 mmol) was added. The rxn mixture was stirred and allowed to warm to room temperature gradually over 16 hours. LCMS showed product formation (m / z values, 256.1, 300.1). The reaction mixture was diluted with water. The product was extracted with DCM. The DCM layer was separated and dried over anhydrous Na2SO4. Evaporation of the solvent gave 0.88 g of product (yield). C 17 H 25 Calculated MS(ESI) mass for NO5S is 355.45; [M-Boc] + The m / z values ​​were 256.1 and 300.1. Step 2: Synthesis of HBS-055-091: Compound HBS-055-090 (0.88 g, 2.48 mmol) and 2-(1H-pyrazol-4-yl)pyridine dihydrochloride (0.6 g, 2.73 mmol) were dissolved in dry DMF (10.0 mL). Anhydrous Cs2CO3 (1.61 g, 4.97 mmol) was added, and the rxn mixture was stirred at 70 °C for 16 hours. LCMS showed product formation (m / z value, 329.2). The rxn mixture was cooled to ambient temperature and diluted with water. The product was extracted with ethyl acetate. The combined EtOAc layers were separated and dried over anhydrous Na2SO4. The crude product was obtained by evaporating the solvent. The crude product was purified by column chromatography (mobile phase: EtOAc:hexane gradient). 0.82 g of pure product was obtained (81.5% yield). C 18 H 24 Calculated MS(ESI) mass for N4O2 is 328.41; [M+H] + The m / z value of was 329.2. Step 3: Synthesis of HBS-055-092: Compound HBS-055-091 (0.82 g, 2.48 mmol) was dissolved in dry dioxane (10.0 mL). 4.0 M HCl solution in dioxane (2.5 mL, 9.94 mmol) was added, and the rxn mixture was stirred at 50° C. for 12 hours. LCMS showed product formation (m / z value, 229.2). The rxn mixture was cooled, and the precipitate was filtered. The precipitate was dried to give 0.75 g of solid product (yield). C 13 H 16 Calculated MS(ESI) mass for N4 is 228.29; [M+H] + The m / z value of was 229.1. [ka] Step 1: Synthesis of HBS-055-093: N-Boc-L-prolinol (0.5 g, 2.48 mmol) was dissolved in DCM (10.0 mL). DIPEA (0.9 mL, 4.97 mmol) was added, followed by DMAP (0.61 g, 4.97 mmol). The rxn mixture was cooled to 0°C in an ice bath. p-TsCl (0.52 g, 2.73 mmol) was added. The rxn mixture was stirred and allowed to warm gradually to room temperature for 16 hours. LCMS showed product formation (m / z values, 256.1, 300.1). The reaction mixture was diluted with water. The product was extracted with DCM. The DCM layer was separated and dried over anhydrous Na2SO4. Evaporation of the solvent gave 0.88 g of product (yield). C 17 H 25 Calculated MS(ESI) mass for NO5S is 355.45; [M-Boc] + The m / z values ​​were 256.1 and 300.1. Step 2: Synthesis of HBS-055-094: Compound HBS-055-093 (0.88 g, 2.48 mmol) and 2-(1H-pyrazol-3-yl)pyridine (0.43 g, 2.98 mmol) were dissolved in dry DMF (10.0 mL). Anhydrous CsCO (1.62 g, 4.97 mmol) was added, and the rxn mixture was stirred at 70 °C for 12 hours. LCMS showed product formation (m / z value, 329.2). The rxn mixture was cooled to ambient temperature and diluted with water. The product was extracted with ethyl acetate. The combined EtOAc layers were separated and dried over anhydrous NaSO. The crude product was obtained by evaporating the solvent. The crude product was purified by column chromatography (mobile phase: EtOAc:hexane gradient). Yield: 0.81 g of product. C 18 H 24 Calculated MS(ESI) mass for N4O2 is 328.41; [M+H] + The m / z value of was 329.2. Step 3: Synthesis of HBS-055-097: Compound HBS-055-094 (0.81 g, 2.48 mmol) was dissolved in dry dioxane (10.0 mL). 4.0 M HCl solution in dioxane (2.5 mL, 9.93 mmol) was added, and the rxn mixture was stirred at 50° C. for 12 hours. LCMS showed product formation (m / z value, 229.2). The rxn mixture was cooled, and the precipitate was filtered. The precipitate was dried to give 0.75 g of solid product (yield). C 13 H 16 Calculated MS(ESI) mass for N4 is 228.29; [M+H] + The m / z value of was 229.1. [ka] Step 1: Synthesis of HBS-055-095: N-Boc-L-prolinol (0.5 g, 2.48 mmol) was dissolved in DCM (10.0 mL). DIPEA (0.9 mL, 4.97 mmol) was added, followed by DMAP (0.61 g, 4.97 mmol). The rxn mixture was cooled to 0°C in an ice bath. p-TsCl (0.52 g, 2.73 mmol) was added. The rxn mixture was stirred and allowed to warm to room temperature gradually for 16 hours. LCMS showed product formation (m / z values, 256.1, 300.1). The reaction mixture was diluted with water. The product was extracted with DCM. The DCM layer was separated and dried over anhydrous Na2SO4. Evaporation of the solvent gave 0.88 g of product (yield). C 17 H 25 Calculated MS(ESI) mass for NO5S is 355.45; [M-Boc] + The m / z values ​​were 256.1 and 300.1. Step 2: Synthesis of HBS-055-096: Compound HBS-055-095 (0.88 g, 2.48 mmol) and 4-phenyl-1H-pyrazole (0.72 g, 4.97 mmol) were dissolved in dry DMF (10.0 mL). Anhydrous Cs2CO3 (1.62 g, 4.97 mmol) was added, and the rxn mixture was stirred at 70 °C for 16 hours. LCMS showed product formation (m / z value, 328.2). The rxn mixture was cooled to ambient temperature and diluted with water. The product was extracted with ethyl acetate. The combined EtOAc layers were separated and dried over anhydrous Na2SO4. The crude product was obtained by evaporating the solvent. The crude product was purified by column chromatography (mobile phase: EtOAc:hexane gradient). 0.6 g of pure product was obtained (73.8% yield). C 19 H 25 Calculated MS(ESI) mass for N3O2 is 327.42; [M+H] + The m / z value of was 328.2. Step 3: Synthesis of HBS-055-098: Compound HBS-055-096 (0.6 g, 1.83 mmol) was dissolved in dry dioxane (10.0 mL). 4.0 M HCl solution in dioxane (1.83 mL, 7.33 mmol) was added, and the rxn mixture was stirred at 50° C. for 12 hours. LCMS showed product formation (m / z value, 228.2). The rxn mixture was cooled, and the precipitate was filtered. The precipitate was dried to give 0.48 g of solid product (yield). C 14 H 17 Calculated MS(ESI) mass for N3 is 227.31; [M+H] + The m / z value of was 228.2. [ka] Step 1: Synthesis of HBS-055-102: N-Boc-L-prolinol (0.5 g, 2.48 mmol) was dissolved in DCM (10.0 mL). DIPEA (0.9 mL, 4.97 mmol) was added, followed by DMAP (0.61 g, 4.97 mmol). The rxn mixture was cooled to 0°C in an ice bath. p-TsCl (0.52 g, 2.73 mmol) was added. The rxn mixture was stirred and allowed to warm to room temperature gradually over 16 hours. LCMS showed product formation (m / z values, 256.1, 300.1). The reaction mixture was diluted with water. The product was extracted with DCM. The DCM layer was separated and dried over anhydrous Na2SO4. Evaporation of the solvent gave 0.88 g of product (yield). C 17 H 25 Calculated MS(ESI) mass for NO5S is 355.45; [M-Boc] + The m / z values ​​were 256.1 and 300.1. Step 2: Synthesis of HBS-055-103: Compound HBS-055-102 (0.88 g, 2.48 mmol) and 5-fluoro-2-(1H-pyrazol-4-yl)pyridine (0.7 g, 2.98 mmol) were dissolved in dry DMF (10.0 mL). Anhydrous Cs2CO3 (2.64 g, 8.1 mmol) was added, and the rxn mixture was stirred at 80 °C for 16 hours. LCMS showed product formation (m / z value, 347.2). The rxn mixture was cooled to ambient temperature and diluted with water. The product was extracted with ethyl acetate. The combined EtOAc layers were separated and dried over anhydrous Na2SO4. The crude product was obtained by evaporating the solvent. The crude product was purified by column chromatography (mobile phase: EtOAc:hexane gradient). 0.45 g of pure product was obtained (52.3% yield). C 18 H 23 Calculated MS(ESI) mass for FN4O2 is 346.4; [M+H] + The m / z value of was 347.2. Step 3: Synthesis of HBS-055-109: Compound HBS-055-103 (0.45 g, 1.3 mmol) was dissolved in dry dioxane (10.0 mL). 4.0 M HCl solution in dioxane (1.3 mL, 5.2 mmol) was added, and the rxn mixture was stirred at 50° C. for 6 hours. LCMS showed product formation (m / z value, 246.28). The rxn mixture was cooled, and the precipitate was filtered. The precipitate was dried to give 0.21 g of solid product (yield 50.6%). 13 H 15 The calculated MS(ESI) mass for FN4 is 246.28; [M+H] + The m / z value of was 247.1. [ka] Step 1: Synthesis of HBS-055-120: (1R,3S,4S)-2-(Tert-butoxycarbonyl)-2-azabicyclo[2.2.1]heptane-3-carboxylic acid (0.5 g, 2.1 mmol) was dissolved in dry THF (10.0 mL). At 0 °C, 2.0 M BH3·Me2S (2.1 mL, 4.14 mmol) was added. The rxn mixture was gradually warmed to ambient temperature for 16 h. LCMS showed product formation (m / z values, 172.1, 250.1). The rxn mixture was quenched with methanol. The reaction mixture was diluted with water. The product was extracted with ethyl acetate. The EtOAc layer was separated and dried over anhydrous Na2SO4. Evaporation of the solvent gave 0.47 g of crude product (yield). C 12 H 21 Calculated MS(ESI) mass for NO3 is 227.3; [M+Na] + The m / z values ​​were 172.1 and 250.1. Step 2: Synthesis of HBS-055-123: Compound HBS-055-120 (0.47 g, 2.1 mmol) was dissolved in dry THF (10.0 mL). NaH (0.166 g, 4.14 mmol) was added at a temperature of 0°C. 2-Chloro-5-trifluoromethylpyridine (0.45 g, 2.48 mmol) was added, and the reaction mixture was gradually heated at reflux for 16 hours. LCMS showed the formation of the product (m / z value, 373.1). The rxn mixture was diluted with water. The product was extracted with ethyl acetate. The combined EtOAc layers were separated and dried over anhydrous Na2SO4. The crude product was obtained by evaporating the solvent. The crude product was purified by column chromatography (mobile phase: EtOAc:hexane gradient). 0.5 g of pure product was obtained (yield 64.9%). C 18 H 23 Calculated MS(ESI) mass for F3N2O3 is 372.38; [M+H] + The m / z value of was 373.1. Step 3: Synthesis of HBS-055-127: Compound HBS-055-123 (0.5 g, 1.34 mmol) was dissolved in dioxane (10.0 mL). 4.0 M HCl solution in dioxane (1.34 mL, 5.37 mmol) was added, and the rxn mixture was stirred at 50° C. for 16 hours. LCMS showed product formation (m / z value, 273.1). The rxn mixture was cooled, and the precipitate was filtered. The precipitate was dried to give 0.41 g of solid product (88.4% yield). 13 H 15 Calculated MS(ESI) mass for FNO is 272.27; [M+H] + The m / z value of was 273.1. [ka] Step 1: Synthesis of HBS-055-140: N-Boc-L-prolinol (0.25 g, 1.24 mmol) was dissolved in DCM (5.0 mL). DIPEA (0.43 mL, 2.48 mmol) was added, followed by DMAP (0.3 g, 2.48 mmol). The rxn mixture was cooled to 0°C in an ice bath. p-TsCl (0.26 g, 1.34 mmol) was added. The rxn mixture was stirred and allowed to warm to room temperature gradually for 16 hours. LCMS showed product formation (m / z values, 256.1, 300.1). The reaction mixture was diluted with water. The product was extracted with DCM. The DCM layer was separated and dried over anhydrous Na2SO4. Evaporation of the solvent gave 0.44 g of product (yield). C 17 H 25 Calculated MS(ESI) mass for NO5S is 355.45; [M-Boc] + The m / z values ​​were 256.1 and 300.1. Step 2: Synthesis of HBS-055-141: Compound HBS-055-140 (0.44 g, 1.24 mmol) and 5-fluoro-2-(1H-pyrazol-3-yl)pyridine (0.24 g, 1.49 mmol) were dissolved in dry DMF (8.0 mL). Anhydrous Cs2CO3 (1.21 g, 3.73 mmol) was added, and the rxn mixture was stirred at 70 °C for 16 hours. LCMS showed product formation (m / z value, 347.2). The rxn mixture was cooled to ambient temperature and diluted with water. The product was extracted with ethyl acetate. The combined EtOAc layers were separated and dried over anhydrous Na2SO4. The crude product was obtained by evaporating the solvent. The crude product was purified by column chromatography (mobile phase: EtOAc:hexane gradient). 0.42 g of pure product was obtained (yield 97.2%). C 18 H 23 Calculated MS(ESI) mass for FN4O2 is 346.4; [M+H] + The m / z value of was 347.2. Step 3: Synthesis of HBS-055-143: Compound HBS-055-141 (0.42 g, 1.21 mmol) was dissolved in dry dioxane (10.0 mL). 4.0 M HCl solution in dioxane (1.21 mL, 4.83 mmol) was added, and the rxn mixture was stirred at 50° C. for 12 hours. LCMS showed product formation (m / z value, 247.1). The rxn mixture was cooled, and the precipitate was filtered. The precipitate was dried to give 0.38 g of solid product (yield 98.6%). 13 H 15 The calculated MS(ESI) mass for FN4 is 246.28; [M+H] + The m / z value of was 247.1. [ka] Step 1: Synthesis of HBS-055-131: (1S,3S,5S)-2-(Tert-butoxycarbonyl)-2-azabicyclo[3.1.0]heptane-3-carboxylic acid (1.0 g, 4.4 mmol) was dissolved in dry THF (10.0 mL). At 0 °C, 2.0 M BH3·Me2S (4.4 mL, 8.8 mmol) was added. The rxn mixture was gradually warmed to ambient temperature for 16 h. LCMS showed product formation (m / z value, 158.1). The rxn mixture was quenched with methanol. The reaction mixture was diluted with water. The product was extracted with ethyl acetate. The EtOAc layer was separated and dried over anhydrous Na2SO4. Evaporation of the solvent gave 0.94 g of crude product (yield). C 11 H 19 Calculated MS(ESI) mass for NO3 is 213.27; [M-Boc] + The m / z value of was 158.1. Step 2: Synthesis of HBS-055-139: Compound HBS-055-131 (0.25 g, 1.17 mmol) was dissolved in DCM (10.0 mL). DIPEA (0.4 mL, 2.34 mmol) was added, followed by DMAP (0.24 g, 2.34 mmol). The rxn mixture was cooled to 0°C in an ice bath. p-TsCl (0.25 g, 1.29 mmol) was added. The rxn mixture was stirred and gradually warmed to room temperature for 16 hours. LCMS showed product formation (m / z values, 268.1, 312.1). The reaction mixture was diluted with water. The product was extracted with DCM. The DCM layer was separated and dried over anhydrous Na2SO4. Evaporation of the solvent gave 0.4 g of product (yield). C 18 H 25 Calculated MS(ESI) mass for NO5S is 367.46; [M-Boc] + The m / z values ​​were 268.1 and 312.1. Step 3: Synthesis of HBS-055-142: Compound HBS-055-139 (0.4 g, 1.1 mmol) and 3-(4-fluorophenyl)-1H-pyrazole (0.2 g, 1.21 mmol) were dissolved in dry DMF (8.0 mL). Anhydrous Cs2CO3 (1.1 g, 3.3 mmol) was added, and the reaction mixture was stirred at 70 °C for 16 hours. LCMS showed product formation (m / z value, 358.2). The rxn mixture was cooled to ambient temperature and diluted with water. The product was extracted with ethyl acetate. The combined EtOAc layers were separated and dried over anhydrous Na2SO4. The crude product was obtained by evaporating the solvent. The crude product was purified by column chromatography (mobile phase: EtOAc:hexane gradient). 0.24 g of pure product was obtained (61.5% yield). C 20 H 24 Calculated MS(ESI) mass for FN3O2 is 357.42; [M+H] + The m / z value of was 358.2. Step 4: Synthesis of HBS-055-147: Compound HBS-055-141 (0.24 g, 0.68 mmol) was dissolved in dry dioxane (5.0 mL). 4.0 M HCl solution in dioxane (1.35 mL, 2.71 mmol) was added, and the rxn mixture was stirred at 50° C. for 16 hours. LCMS showed product formation (m / z value, 258.1). The rxn mixture was cooled, and the precipitate was filtered. The precipitate was dried to give 0.19 g of solid product (yield 95.5%). 15 H 16 The calculated MS(ESI) mass for FN3 is 257.31; [M+H] + The m / z value of was 258.1. [ka] Step 1: Synthesis of HBS-055-154: (S)-1-(tert-butoxycarbonyl)-2-azetidinemethanol (0.5 g, 2.67 mmol) was dissolved in DCM (10.0 mL). DIPEA (0.93 mL, 5.34 mmol) was added, followed by DMAP (0.65 g, 5.34 mmol). The rxn mixture was cooled to 0°C in an ice bath. p-TsCl (0.56 g, 2.94 mmol) was added. The rxn mixture was stirred and allowed to warm to room temperature gradually over 16 hours. LCMS showed product formation (m / z values, 242.1, 286.1). The reaction mixture was diluted with water. The product was extracted with DCM. The DCM layer was separated and dried over anhydrous Na2SO4. Evaporation of the solvent gave 0.91 g of product (yield). C 16 H 23 Calculated MS(ESI) mass for NO5S is 341.42; [M-Boc] + The m / z values ​​were 242.1 and 286.1. Step 2: Synthesis of HBS-055-155: Compound HBS-055-154 (0.91 g, 2.67 mmol) and 3-(4-fluorophenyl)-1H-pyrazole (0.48 g, 0.48 mmol) were dissolved in dry DMF (10.0 mL). Anhydrous Cs2CO3 (2.61 g, 8.01 mmol) was added, and the reaction mixture was stirred at 70 °C for 16 hours. LCMS showed product formation (m / z value, 332.2). The rxn mixture was cooled to ambient temperature and diluted with water. The product was extracted with ethyl acetate. The combined EtOAc layers were separated and dried over anhydrous Na2SO4. The crude product was obtained by evaporating the solvent. The crude product was purified by column chromatography (mobile phase: EtOAc:hexane gradient). Yield: 0.89 g of pure product was obtained. C 18 H 22 Calculated MS(ESI) mass for FN3O2 is 331.38; [M+H] + The m / z value of was 332.2. Step 3: Synthesis of HBS-055-158: Compound HBS-055-155 (0.89 g, 2.67 mmol) was dissolved in dry dioxane (10.0 mL). 4.0 M HCl solution in dioxane (2.7 mL, 10.68 mmol) was added, and the rxn mixture was stirred at 50° C. for 16 hours. LCMS showed product formation (m / z value, 232.1). The rxn mixture was cooled and concentrated under reduced pressure to give 0.72 g of solid product (yield). 13 H 14 The calculated MS(ESI) mass for FN3 is 231.27; [M+H] + The m / z value of was 232.1. [ka] Step 1: Synthesis of HBS-055-156: (S)-1-(tert-butoxycarbonyl)-2-azetidinemethanol (0.25 g, 1.33 mmol) was dissolved in DCM (8.0 mL). DIPEA (0.47 mL, 2.67 mmol) was added, followed by DMAP (0.33 g, 2.67 mmol). The rxn mixture was cooled to 0°C in an ice bath. p-TsCl (0.28 g, 1.47 mmol) was added. The rxn mixture was stirred and allowed to warm gradually to room temperature for 16 hours. LCMS showed product formation (m / z values, 242.1, 286.1). The reaction mixture was diluted with water. The product was extracted with DCM. The DCM layer was separated and dried over anhydrous Na2SO4. Evaporation of the solvent gave 0.46 g of product (yield). C 16 H 23 Calculated MS(ESI) mass for NO5S is 341.42; [M-Boc] + The m / z values ​​were 242.1 and 286.1. Step 2: Synthesis of HBS-055-157: Compound HBS-055-156 (0.46 g, 1.33 mmol) and 5-fluoro-2-(1H-pyrazol-3-yl)pyridine (0.26 g, 1.60 mmol) were dissolved in dry DMF (10.0 mL). Anhydrous Cs2CO3 (1.31 g, 4.0 mmol) was added, and the reaction mixture was stirred at 70 °C for 16 hours. LCMS showed the product formation (m / z value, 333.1). The rxn mixture was cooled to ambient temperature and diluted with water. The product was extracted with ethyl acetate. The combined EtOAc layers were separated and dried over anhydrous Na2SO4. The crude product was obtained by evaporating the solvent. The crude product was purified by column chromatography (mobile phase: EtOAc:hexane gradient). Yield: 0.44 g of pure product was obtained. C 17 H 21 Calculated MS(ESI) mass for FN4O2 is 332.37; [M+H] + The m / z value of was 333.1. Step 3: Synthesis of HBS-055-162: Compound HBS-055-157 (0.44 g, 1.34 mmol) was dissolved in dry dioxane (10.0 mL). 4.0 M HCl solution in dioxane (1.34 mL, 5.34 mmol) was added, and the rxn mixture was stirred at 40° C. for 16 hours. LCMS showed product formation (m / z value, 233.1). The rxn mixture was cooled and concentrated under reduced pressure to give 0.41 g of product (yield). 12 H 13 The calculated MS(ESI) mass for FN4 is 232.26; [M+H] + The m / z value of was 233.1. [ka] Step 1: Synthesis of HBS-055-168: Compound HBS-055-131 (0.25 g, 1.17 mmol) was dissolved in DCM (10.0 mL). DIPEA (0.4 mL, 2.34 mmol) was added, followed by DMAP (0.24 g, 2.34 mmol). The rxn mixture was cooled to 0°C in an ice bath. p-TsCl (0.25 g, 1.29 mmol) was added. The rxn mixture was stirred and gradually warmed to room temperature for 16 hours. LCMS showed product formation (m / z values, 268.1, 312.1). The reaction mixture was diluted with water. The product was extracted with DCM. The DCM layer was separated and dried over anhydrous Na2SO4. Evaporation of the solvent gave 0.43 g of product (yield). C 18 H 25 Calculated MS(ESI) mass for NO5S is 367.46; [M-Boc] + The m / z values ​​were 268.1 and 312.1. Step 2: Synthesis of HBS-055-169: Compound HBS-055-168 (0.43 g, 1.17 mmol) and 5-fluoro-2-(1H-pyrazol-3-yl)pyridine (0.23 g, 1.41 mmol) were dissolved in dry DMF (8.0 mL). Anhydrous Cs2CO3 (1.15 g, 3.52 mmol) was added, and the reaction mixture was stirred at 70 °C for 16 hours. LCMS showed product formation (m / z value, 359.2). The rxn mixture was cooled to ambient temperature and diluted with water. The product was extracted with ethyl acetate. The combined EtOAc layers were separated and dried over anhydrous Na2SO4. The crude product was obtained by evaporating the solvent. The crude product was purified by column chromatography (mobile phase: EtOAc:hexane gradient). 0.23 g of pure product was obtained (yield: 53.8%). C 19 H 23 Calculated MS(ESI) mass for FN4O2 is 358.41; [M+H] + The m / z value of was 359.2. Step 3: Synthesis of HBS-055-170: Compound HBS-055-169 (0.23 g, 0.63 mmol) was dissolved in dry dioxane (6.0 mL). 4.0 M HCl solution in dioxane (0.63 mL, 2.52 mmol) was added, and the rxn mixture was stirred at 50° C. for 16 hours. LCMS showed product formation (m / z value, 259.1). The rxn mixture was cooled, and the precipitate was filtered. The precipitate was dried to give 0.19 g of solid product (yield 90.95%). 14 H 15 The calculated MS(ESI) mass for FN4 is 258.29; [M+H] + The m / z value of was 259.1. [ka] Step 1: Synthesis of HBS-055-179: (R)-3-Hydroxymethyl-4-Boc-morpholine (0.5 g, 2.3 mmol) was dissolved in dry THF (10.0 mL). At 0 °C, NaH (0.14 g, 3.45 mmol) was added. 2-Chloro-5-trifluoromethylpyridine (0.5 g, 2.76 mmol) was added, and the reaction mixture was gradually heated at reflux for 16 h. LCMS showed the formation of two products (m / z = 363.1 and m / z = 263.1). The rxn mixture was diluted with water. The product was extracted with ethyl acetate. The combined EtOAc layers were separated and dried over anhydrous Na2SO4. The crude product was obtained by evaporation of the solvent. The crude product was purified by column chromatography (mobile phase: EtOAc:hexane gradient and DCM:MeOH gradient). 0.39 g of pure product A was obtained (46.8% yield); and 0.12 g of deboc product B was obtained (19.9% ​​yield). 16 H 21 Calculated MS(ESI) mass for F3N2O4 is 362.34; [M+H] + The m / z value of C was 363.1. 11 H 13 Calculated MS(ESI) mass for F3N2O2 is 262.23; [M+H] + The m / z value of was 263.1. Step 2: Synthesis of HBS-055-180: Compound HBS-055-179A (0.39 g, 1.08 mmol) was dissolved in dioxane (6.0 mL). 4.0 M HCl solution in dioxane (1.1 mL, 4.31 mmol) was added, and the rxn mixture was stirred at 50° C. for 16 hours. LCMS showed product formation (m / z value, 263.0). The rxn mixture was cooled, and the precipitate was filtered. The precipitate was dried to give 0.33 g of pure product (91.5% yield). C 11 H 13 Calculated MS(ESI) mass for F3N2O2 is 262.23; [M+H] + The m / z value of was 263.0. [ka] Step 1: Synthesis of HBS-062-054: Compound HBS-062-051 (0.9 g, 4.18 mmol) was dissolved in DCM (15.0 mL). DIPEA (1.1 mL, 6.27 mmol) was added, followed by DMAP (0.77 g, 6.27 mmol). The rxn mixture was cooled to 0°C in an ice bath. p-TsCl (0.88 g, 4.6 mmol) was added. The rxn mixture was stirred and allowed to warm to room temperature gradually for 16 hours. LCMS showed product formation (m / z values, 270.1, 314.1). The reaction mixture was diluted with water. The product was extracted with DCM. The DCM layer was separated and dried over anhydrous Na2SO4. Evaporation of the solvent gave 1.54 g of product (yield). C 18 H 27 Calculated MS(ESI) mass for NO5S is 369.48; [M-Boc] + The m / z values ​​were 270.1 and 314.1. Step 2: Synthesis of HBS-062-055: Compound HBS-062-054 (1.54 g, 4.17 mmol) and 2-(1H-pyrazol-3-yl)pyridine (0.61 g, 4.17 mmol) were dissolved in dry DMF (12.0 mL). Anhydrous Cs2CO3 (4.1 g, 12.5 mmol) was added, and the reaction mixture was stirred at 70 °C for 12 hours. LCMS showed the formation of the product (m / z value, 343.2) and other by-products. The rxn mixture was cooled to ambient temperature and diluted with water. The product was extracted with ethyl acetate. The combined EtOAc layers were separated and dried over anhydrous Na2SO4. The crude product was obtained by evaporating the solvent. The crude product was purified by column chromatography (mobile phase: EtOAc:hexane gradient). 0.12 g of pure product was obtained (yield: 8.41%). C 19 H 26 Calculated MS(ESI) mass for N4O2 is 342.44; [M+H] + The m / z value of was 343.2. Step 3: Synthesis of HBS-062-063: Compound HBS-062-055 (0.12 g, 0.35 mmol) was dissolved in dry dioxane (5.0 mL). 4.0 M HCl solution in dioxane (0.4 mL, 1.75 mmol) was added, and the rxn mixture was stirred at 50° C. for 6 hours. LCMS showed product formation (m / z value, 243.1). The rxn mixture was cooled and the solvent was concentrated to give 0.067 g of solid product (60.7% yield). 14 H 18 Calculated MS(ESI) mass for N4 is 242.32; [M+H] + The m / z value of was 243.1. [ka] Step 1: Synthesis of HBS-062-051: N-Boc-alpha-methyl-L-proline (4.0 g, 17.44 mmol) was dissolved in dry THF (20.0 mL). At 0 °C, 2.0 M BH3·Me2S (17.4 mL, 34.9 mmol) was added. The rxn mixture was gradually warmed to ambient temperature for 16 h. LCMS showed product formation (m / z value, 160.1). The rxn mixture was quenched with methanol. The reaction mixture was diluted with water. The product was extracted with ethyl acetate. The EtOAc layer was separated and dried over anhydrous Na2SO4. Evaporation of the solvent gave 3.75 g of crude product (yield). C 11 H 21 Calculated MS(ESI) mass for NO3 is 215.29; [M-Boc] + The m / z value of was 160.1. Step 2: Synthesis of HBS-062-060: Compound HBS-062-051 (0.9 g, 4.18 mmol) was dissolved in dry DMF (10.0 mL). At a temperature of 0°C, NaH (0.25 g, 6.27 mmol) was added. 2-Chloro-5-trifluoromethylpyridine (0.76 g, 4.18 mmol) was added, and the reaction mixture was gradually heated at reflux for 5 hours. LCMS showed the formation of the product (m / z value, 361.1). The rxn mixture was diluted with water. The product was extracted with ethyl acetate. The combined EtOAc layers were separated and dried over anhydrous Na2SO4. The crude product was obtained by evaporating the solvent. The crude product was purified by column chromatography (mobile phase: EtOAc:hexane gradient). 0.66 g of product was obtained (yield: 43.8%). C 17 H 23 Calculated MS(ESI) mass for F3N2O3 is 360.37; [M+H] + The m / z value of was 361.1. Step 3: Synthesis of HBS-062-065: Compound HBS-062-060 (0.66 g, 1.83 mmol) was dissolved in dioxane (8.0 mL). 4.0 M HCl solution in dioxane (1.83 mL, 7.33 mmol) was added, and the rxn mixture was stirred at 50° C. for 16 hours. LCMS showed product formation (m / z value, 261.1). The rxn mixture was cooled, and the precipitate was filtered. The precipitate was dried to give 0.46 g of pure product (75.4% yield). C 12 H 15 Calculated MS(ESI) mass for FNO is 260.26; [M+H] + The m / z value of was 261.1. [ka] Step 1: Synthesis of HBS-062-114: Tert-butyl-1-(hydroxymethyl)-7-azabicyclo[2.2.1]heptane-7-carboxylate (0.2 g, 0.88 mmol) was dissolved in dry DMF (6.0 mL). At 0°C, NaH (0.052 g, 1.32 mmol) was added. 2-Chloro-5-trifluoromethylpyridine (0.24 g, 1.32 mmol) was added, and the reaction mixture was gradually heated at 75°C for 8 hours. LCMS showed the formation of the product (m / z value, 373.1). The rxn mixture was diluted with water. The product was extracted with ethyl acetate. The combined EtOAc layers were separated and dried over anhydrous NaSO. The crude product was obtained by evaporating the solvent. The crude product was purified by column chromatography (mobile phase: EtOAc:hexane gradient). Yield: 0.33 g of product. C 18 H 23 Calculated MS(ESI) mass for F3N2O3 is 372.38; [M+H] + The m / z value of was 373.1. Step 2: Synthesis of HBS-062-116: Compound HBS-062-114 (0.33 g, 0.88 mmol) was dissolved in dioxane (5.0 mL). 4.0 M HCl solution in dioxane (0.88 mL, 3.52 mmol) was added, and the rxn mixture was stirred at 50° C. for 8 hours. LCMS showed product formation (m / z value, 273.1). The rxn mixture was cooled and concentrated under reduced pressure to give 0.28 g of pure product (92.2% yield). 13 H 15 Calculated MS(ESI) mass for FNO is 272.27; [M+H] + The m / z value of was 273.1. [ka] Step 1: Synthesis of HBS-062-134: N-Boc-alpha-methyl-L-proline (5.0 g, 21.81 mmol) was dissolved in dry THF (20.0 mL). At 0 °C, 2.0 M BH3·Me2S (21.8 mL, 43.62 mmol) was added. The rxn mixture was gradually warmed to ambient temperature for 16 h. LCMS showed product formation (m / z value, 160.0). The rxn mixture was quenched with methanol. The reaction mixture was diluted with water. The product was extracted with ethyl acetate. The EtOAc layer was separated and dried over anhydrous Na2SO4. Evaporation of the solvent gave 4.3 g of crude product (yield). C 11 H 21 Calculated MS(ESI) mass for NO3 is 215.29; [M-Boc] + The m / z value of was 160.1. Step 2: Synthesis of HBS-062-138: Compound HBS-062-134 (0.5 g, 2.32 mmol) was dissolved in dry THF (6.0 mL). At a temperature of 0°C, NaH (0.14 g, 3.49 mmol) was added. 2-Chloro-5-trifluoromethylpyrazine (0.3 mL, 2.32 mmol) was added, and the reaction mixture was gradually heated at reflux for 6 hours. LCMS showed the formation of the product (m / z values, 262.1, 306.0). The rxn mixture was diluted with water. The product was extracted with ethyl acetate. The combined EtOAc layers were separated and dried over anhydrous Na2SO4. The crude product was obtained by evaporating the solvent. The crude product was purified by column chromatography (mobile phase: EtOAc:hexane gradient). 0.44 g of product was obtained (yield 52.4%). C 16 H 22 Calculated MS(ESI) mass for F3N3O3 is 361.36; [M-Boc] + The m / z values ​​were 262.1 and 306.0. Step 3: Synthesis of HBS-062-142: Compound HBS-062-138 (0.44 g, 1.22 mmol) was dissolved in dioxane (5.0 mL). 4.0 M HCl solution in dioxane (1.52 mL, 6.1 mmol) was added, and the rxn mixture was stirred at 50° C. for 8 hours. LCMS showed product formation (m / z value, 262.1). The rxn mixture was cooled and concentrated under reduced pressure to give 0.37 g of pure product (82.4% yield). 11 H 14 Calculated MS(ESI) mass for FNO is 261.24; [M+H] + The m / z value of was 262.1. [ka] Step 1: Synthesis of HBS-062-150: L-Proline (0.58 g, 5.0 mmol) and NaOH (0.6 g, 15.0 mmol) were dissolved in DO (5.0 mL). Ru / C 5 wt.% (0.058 g, 10% w / w) was added, and the reaction mixture was stirred under a hydrogen atmosphere at 70 °C for 6 hours. LCMS showed product formation (m / z value, 118.1). The rxn mixture was filtered through a bed of Celite and washed with DO. The pH of the reaction mixture was adjusted to 6.5 with HCl. Dowex X-8 [H+] resin was added, and the aqueous layer was filtered and washed with 25% aqueous ammonia. The aqueous layer was concentrated under reduced pressure to give 0.59 g of crude product (yield). MS (ESI) mass calculated for CHDNO was 118.15; [M+H] + The m / z value of was 118.1. Step 2: Synthesis of HBS-062-155: Compound HBS-062-150 (0.59 g, 5.0 mmol) was dissolved in DCM (15.0 mL). Triethylamine (0.76 mL, 5.5 mmol) was added, followed by di-tert-butyl dicarbonate (1.2 g, 5.5 mmol). The rxn mixture was stirred at ambient temperature for 16 h. LCMS showed product formation (m / z value, 162.0). The reaction mixture was diluted with water. The product was extracted with DCM. The DCM layer was separated and dried over anhydrous Na2SO4. Evaporation of the solvent and extraction of the aqueous layer afforded 0.95 g of the combined product (87.1% yield). C10 H 14 Calculated MS(ESI) mass for D3NO4 is 218.26; [MtButyl] + The m / z value of was 162.0. Step 3: Synthesis of HBS-062-156: Compound HBS-062-155 (0.95 g, 4.35 mmol) was dissolved in dry THF (10.0 mL). At a temperature of 0 °C, 2.0 M BH3·Me2S (4.3 mL, 8.70 mmol) was added. The rxn mixture was gradually warmed to ambient temperature for 16 h. LCMS showed product formation (m / z value, 148.1). The rxn mixture was quenched with methanol. The reaction mixture was diluted with water. The product was extracted with ethyl acetate. The EtOAc layer was separated and dried over anhydrous Na2SO4. The crude product was purified by column chromatography (mobile phase: EtOAc:hexane gradient). 0.8 g of product was obtained (yield 90.0%). C 10 H 16 Calculated MS(ESI) mass for D3NO3 is 204.28; [MtButyl] + The m / z value of was 148.1. Step 4: Synthesis of HBS-062-163: Compound HBS-062-156 (0.4 g, 1.96 mmol) was dissolved in dry THF (10.0 mL). At a temperature of 0° C., NaH (0.12 g, 2.49 mmol) was added. 2-Chloro-5-trifluoromethylpyridine (0.53 g, 2.94 mmol) was added, and the reaction mixture was gradually heated at reflux for 6 hours. LCMS showed the formation of the product (m / z value, 350.1). The rxn mixture was diluted with water. The product was extracted with ethyl acetate. The combined EtOAc layers were separated and dried over anhydrous Na2SO4. The crude product was obtained by evaporating the solvent. The crude product was purified by column chromatography (mobile phase: EtOAc:hexane gradient). 0.6 g of product was obtained (yield 87.7%). C 16 H 18 Calculated MS(ESI) mass for D3F3N2O3 is 349.36; [M+H] + The m / z value of was 350.1. Step 5: Synthesis of HBS-062-166: Compound HBS-062-163 (0.6 g, 1.72 mmol) was dissolved in dioxane (8.0 mL). 4.0 M HCl solution in dioxane (2.15 mL, 8.59 mmol) was added, and the rxn mixture was stirred at 55° C. for 8 hours. LCMS showed product formation (m / z value, 250.1). The rxn mixture was cooled to ambient temperature. The precipitate was filtered and dried to give 0.49 g of pure product (88.5% yield). 11 H 10 Calculated MS(ESI) mass for D3F3N2O is 249.25; [M+H] + The m / z value of was 250.1. [ka] Step 1: Synthesis of HBS-062-167: Compound HBS-062-156 (0.4 g, 1.96 mmol) was dissolved in DCM (15.0 mL). DIPEA (0.51 mL, 2.94 mmol) was added, followed by DMAP (0.36 g, 2.94 mmol). The rxn mixture was cooled to 0°C in an ice bath. p-TsCl (0.41 g, 2.15 mmol) was added. The rxn mixture was stirred and allowed to warm gradually to room temperature for 24 hours. LCMS showed product formation (m / z values, 258.1, 302.1). The reaction mixture was diluted with water. The product was extracted with DCM. The DCM layer was separated and dried over anhydrous Na2SO4. Evaporation of the solvent gave 0.7 g of product (yield). C 17 H 22 Calculated MS(ESI) mass for D3NO5S is 358.47; [M-Boc] + The m / z values ​​were 258.1 and 302.1. Step 2: Synthesis of HBS-062-169: Compound HBS-062-167 (0.7 g, 1.96 mmol) and 3-phenyl-1H-pyrazole (0.34 g, 2.35 mmol) were dissolved in dry 1,4-dioxane (10.0 mL). Anhydrous Cs2CO3 (1.6 g, 4.9 mmol) was added, and the reaction mixture was stirred at reflux temperature for 24 hours. LCMS showed product formation (m / z value, 331.2). The rxn mixture was cooled to ambient temperature and diluted with water. The product was extracted with ethyl acetate. The combined EtOAc layers were separated and dried over anhydrous Na2SO4. The crude product was obtained by evaporating the solvent. The crude product was purified by column chromatography (mobile phase: EtOAc:hexane gradient). 0.58 g of pure product was obtained (89.6% yield). C 19 H 22 Calculated MS(ESI) mass for D3N3O2 is 330.44; [M+H] + The m / z value of was 331.2. Step 3: Synthesis of HBS-062-172: Compound HBS-062-169 (0.58 g, 1.76 mmol) was dissolved in dry dioxane (8.0 mL). 4.0 M HCl solution in dioxane (2.2 mL, 8.78 mmol) was added, and the rxn mixture was stirred at 55° C. for 8 hours. LCMS showed product formation (m / z value, 231.1). The rxn mixture was cooled, and the solvent was concentrated to give 0.47 g of solid product (yield). C 14 H 14 Calculated MS(ESI) mass for D3N3 is 230.32; [M+H] + The m / z value of was 231.1. [ka] Step 1: Synthesis of HBS-062-190: Compound HBS-062-156 (0.5 g, 2.45 mmol) was dissolved in DCM (15.0 mL). DIPEA (0.64 mL, 3.67 mmol) was added, followed by DMAP (0.45 g, 3.67 mmol). The rxn mixture was cooled to 0°C in an ice bath. p-TsCl (0.56 g, 2.94 mmol) was added. The rxn mixture was stirred and allowed to warm to room temperature gradually for 24 hours. LCMS showed product formation (m / z values, 259.1, 303.1). The reaction mixture was diluted with water. The product was extracted with DCM. The DCM layer was separated and dried over anhydrous Na2SO4. Evaporation of the solvent gave 0.82 g of product (93.7% yield). C 17 H 22 Calculated MS(ESI) mass for D3NO5S is 358.47; [M-Boc] + The m / z values ​​were 259.1 and 303.1. Step 2: Synthesis of HBS-062-194: Compound HBS-062-190 (0.8 g, 2.23 mmol) and 3-(4-fluorophenyl)-1H-pyrazole (0.43 g, 2.68 mmol) were dissolved in dry 1,4-dioxane (12.0 mL). Anhydrous Cs2CO3 (1.81 g, 5.58 mmol) was added, and the reaction mixture was stirred at reflux temperature for 24 hours. LCMS showed product formation (m / z value, 349.2). The rxn mixture was cooled to ambient temperature and diluted with water. The product was extracted with ethyl acetate. The combined EtOAc layers were separated and dried over anhydrous Na2SO4. The crude product was obtained by evaporating the solvent. The crude product was purified by column chromatography (mobile phase: EtOAc:hexane gradient). 0.62 g of pure product was obtained (79.7% yield). C 19 H 21 Calculated MS(ESI) mass for D3FN3O2 is 348.43; [M+H] + The m / z value of was 349.2. Step 3: Synthesis of HBS-062-197: Compound HBS-062-194 (0.62 g, 1.78 mmol) was dissolved in dry dioxane (8.0 mL). 4.0 M HCl solution in dioxane (1.8 mL, 7.12 mmol) was added, and the rxn mixture was stirred at 55° C. for 8 hours. LCMS showed product formation (m / z value, 249.2). The rxn mixture was cooled, and the precipitate was filtered. The precipitate was dried to give 0.49 g of solid product (yield 96.7%). 14 H 13 The calculated MS(ESI) mass for D3FN3 is 248.31; [M+H] + The m / z value of was 249.2. [ka] Step 1: Synthesis of HBS-065-037: N-Boc-L-prolinol (1.0 g, 4.97 mmol) was dissolved in DCM (15.0 mL). DIPEA (1.3 mL, 7.45 mmol) was added, followed by DMAP (0.91 g, 7.45 mmol). The rxn mixture was cooled to 0°C in an ice bath. p-TsCl (1.04 g, 5.46 mmol) was added. The rxn mixture was stirred and allowed to warm to room temperature gradually over 16 hours. LCMS showed product formation (m / z values, 256.0, 300.0). The reaction mixture was diluted with water. The product was extracted with DCM. The DCM layer was separated and dried over anhydrous Na2SO4. Evaporation of the solvent gave 1.76 g of product (yield). C 17 H 25 Calculated MS(ESI) mass for NO5S is 355.45; [M-Boc] + The m / z values ​​were 256.0 and 300.0. Step 2: Synthesis of HBS-065-040: Compound HBS-065-037 (1.76 g, 4.97 mmol) and 2-(1H-pyrazol-4-yl-5-(trifluoromethyl)pyridine hydrochloride (1.42 g, 4.97 mmol) were dissolved in dry 1,4-dioxane (25.0 mL). Anhydrous CsCO (3.24 g, 9.94 mmol) was added, and the reaction mixture was stirred at reflux temperature for 24 h. LCMS showed product formation (m / z value, 397.2). The rxn mixture was cooled to ambient temperature and diluted with water. The product was extracted with ethyl acetate. The combined EtOAc layers were separated and dried over anhydrous NaSO. The crude product was obtained by evaporation of the solvent. The crude product was purified by column chromatography (mobile phase: EtOAc:hexane gradient). 1.0 g of pure product was obtained (yield 50.8%). 19 H 23 Calculated MS(ESI) mass for F3N4O2 is 396.41; [M+H] + The m / z value of was 397.2. Step 3: Synthesis of HBS-065-043: Compound HBS-065-040 (1.0 g, 2.52 mmol) was dissolved in dry dioxane (15.0 mL). 4.0 M HCl solution in dioxane (2.52 mL, 10.1 mmol) was added, and the reaction mixture was stirred at 60° C. for 12 hours. LCMS showed product formation (m / z value, 297.1). The rxn mixture was cooled, and the precipitate was filtered. The precipitate was dried to give 0.81 g of solid product (yield 87.0%). 14 H 15 Calculated MS(ESI) mass for F3N4 is 296.29; [M+H] + The m / z value of was 297.1. [ka] Step 1: Synthesis of HBS-065-056: (2S,5S)-tert-butyl-2-(hydroxymethyl)-5-methylpyrrolidine-1-carboxylate (0.25 g, 1.16 mmol) was dissolved in dry THF (6.0 mL). At 0°C, NaH (0.07 g, 1.74 mmol) was added. 2-Chloro-5-trifluoromethylpyridine (0.25 g, 1.39 mmol) was added, and the reaction mixture was heated slowly at reflux for 6 hours. LCMS showed the formation of the product (m / z value, 361.2). The rxn mixture was diluted with water. The product was extracted with ethyl acetate. The combined EtOAc layers were separated and dried over anhydrous Na2SO4. The crude product was obtained by evaporating the solvent. The crude product was purified by column chromatography (mobile phase: EtOAc:hexane gradient). Yield: 0.42 g of product. C 17 H 23 Calculated MS(ESI) mass for F3N2O3 is 360.37; [M+H] + The m / z value of was 361.2. Step 2: Synthesis of HBS-065-058: Compound HBS-065-056 (0.42 g, 1.17 mmol) was dissolved in dioxane (8.0 mL). 4.0 M HCl solution in dioxane (1.16 mL, 4.66 mmol) was added, and the resulting mixture was stirred at 60° C. for 12 hours. LCMS showed product formation (m / z value, 261.1). The reaction mixture was cooled to ambient temperature. The precipitate was filtered and dried to give 0.31 g of pure product (79.8% yield). 12 H 15 Calculated MS(ESI) mass for FNO is 260.26; [M+H] + The m / z value of was 261.1. [ka] Step 1: Synthesis of HBS-065-065: Compound HBS-055-131 (0.5 g, 2.34 mmol) was dissolved in dry THF (8.0 mL). At a temperature of 0° C., NaH (0.14 g, 3.51 mmol) was added. 2-Chloro-5-trifluoromethylpyridine (0.51 g, 2.81 mmol) was added, and the reaction mixture was gradually heated at reflux for 6 hours. LCMS showed the formation of the product (m / z value, 359.1). The rxn mixture was diluted with water. The product was extracted with ethyl acetate. The combined EtOAc layers were separated and dried over anhydrous Na2SO4. The crude product was obtained by evaporating the solvent. The crude product was purified by column chromatography (mobile phase: EtOAc:hexane gradient). 0.6 g of product was obtained (71.5% yield). C 17 H 21 Calculated MS(ESI) mass for F3N2O3 is 358.36; [M+H] + The m / z value of was 359.1. Step 2: Synthesis of HBS-065-067: Compound HBS-065-065 (0.6 g, 1.67 mmol) was dissolved in dioxane (6.0 mL). 4.0 M HCl solution in dioxane (1.67 mL, 6.7 mmol) was added, and the resulting mixture was stirred at 60° C. for 12 hours. LCMS showed the formation of the product (m / z value, 259.0). The reaction mixture was cooled to ambient temperature and concentrated under reduced pressure to give 0.55 g of pure product (yield). 12 H 13 Calculated MS(ESI) mass for FNO is 258.24; [M+H] + The m / z value of was 259.0. [ka] Step 1: Synthesis of HBS-065-119: (1R,3S,5R)-2-[(Tert-butoxy)carbonyl]-2-azabicyclo[3.1.0]hexane-3-carboxylic acid (2.0 g, 8.8 mmol) was dissolved in dry THF (20.0 mL). At 0 °C, 2.0 M BH3·Me2S (8.8 mL, 17.6 mmol) was added. The rxn mixture was gradually warmed to ambient temperature for 16 h. LCMS showed product formation (m / z value, 158.1). The rxn mixture was quenched with methanol. The reaction mixture was diluted with water. The product was extracted with ethyl acetate. The EtOAc layer was separated and dried over anhydrous Na2SO4. Evaporation of the solvent gave 1.88 g of crude product (yield). C 11 H 19 Calculated MS(ESI) mass for NO3 is 213.27; [M-Boc] + The m / z value of was 158.1. Step 2: Synthesis of HBS-065-123: Compound HBS-065-119 (1.86 g, 8.72 mmol) was dissolved in DCM (25.0 mL). DIPEA (2.3 mL, 13.1 mmol) was added, followed by DMAP (1.6 g, 13.1 mmol). The rxn mixture was cooled to 0 °C in an ice bath. p-TsCl (2.0 g, 10.47 mmol) was added. The rxn mixture was stirred and gradually warmed to room temperature for 16 hours. LCMS showed product formation (m / z values, 268.1, 312.1). The reaction mixture was diluted with water. The product was extracted with DCM. The DCM layer was separated and dried over anhydrous Na2SO4. The crude product was obtained by evaporation of the solvent. The crude product was purified by column chromatography (mobile phase: EtOAc:hexane gradient). 2.76 g of product was obtained (yield 86.12%). 18 H 25 Calculated MS(ESI) mass for NO5S is 367.46; [M-Boc] + The m / z values ​​were 268.1 and 312.1. Step 3: Synthesis of HBS-065-126: Compound HBS-065-123 (0.5 g, 1.36 mmol) and 2-(1H-pyrazol-3-yl)pyridine (0.22 g, 1.5 mmol) were dissolved in 1,4-dioxane (8.0 mL). Anhydrous Cs2CO3 (0.89 g, 2.72 mmol) was added, and the reaction mixture was stirred at reflux for 16 hours. LCMS showed product formation (m / z value, 341.2). The rxn mixture was cooled to ambient temperature and diluted with water. The product was extracted with ethyl acetate. The combined EtOAc layers were separated and dried over anhydrous Na2SO4. The crude product was obtained by evaporating the solvent. The crude product was purified by column chromatography (mobile phase: EtOAc:hexane gradient). 0.12 g of pure product was obtained (24.8% yield). C 19 H 24 Calculated MS(ESI) mass for N4O2 is 340.42; [M+H] + The m / z value of was 341.2. Step 4: Synthesis of HBS-065-128: Compound HBS-065-126 (0.12 g, 0.33 mmol) was dissolved in dry dioxane (5.0 mL). 4.0 M HCl solution in dioxane (0.33 mL, 1.35 mmol) was added, and the rxn mixture was stirred at ambient temperature for 24 hours. LCMS showed product formation (m / z value, 241.1). The rxn mixture was cooled, and the precipitate was filtered. The precipitate was dried to give 0.093 g of solid product (87.9% yield). C 14 H 16 Calculated MS(ESI) mass for N4 is 240.3; [M+H] + The m / z value of was 241.1. [ka] Step 1: Synthesis of HBS-065-135: Compound HBS-065-123 (0.5 g, 1.36 mmol) and 2-(1H-pyrazol-4-yl)pyridine (0.22 g, 1.5 mmol) were dissolved in 1,4-dioxane (10.0 mL). Anhydrous CsCO (0.89 g, 2.72 mmol) was added, and the reaction mixture was stirred at reflux for 16 hours. LCMS showed product formation (m / z value, 341.2). The rxn mixture was cooled to ambient temperature and diluted with water. The product was extracted with ethyl acetate. The combined EtOAc layers were separated and dried over anhydrous NaSO. The crude product was obtained by evaporation of the solvent. The crude product was purified by column chromatography (mobile phase: EtOAc:hexane gradient). Yield: 0.46 g of pure product was obtained. C 19 H 24 Calculated MS(ESI) mass for N4O2 is 340.42; [M+H] + The m / z value of was 341.2. Step 4: Synthesis of HBS-065-140: Compound HBS-065-135 (0.46 g, 1.36 mmol) was dissolved in dry dioxane (10.0 mL). 4.0 M HCl solution in dioxane (1.36 mL, 5.44 mmol) was added, and the rxn mixture was stirred at 55° C. for 8 hours. LCMS showed product formation (m / z value, 241.2). The rxn mixture was cooled, and the precipitate was filtered. The precipitate was dried to give 0.38 g of solid product (89.1% yield). C 14 H 16 Calculated MS(ESI) mass for N4 is 240.3; [M+H] + The m / z value of was 241.2. [ka] Step 1: Synthesis of HBS-037-167: [(2S,3R)-1-[4-Methoxyphenyl)methyl]-3-methylpiperidin-2-yl]methanamine (0.1 g, 0.4 mmol) and 2-chloro-5-fluoro-pyrimidine (0.12 g, 0.81 mmol) were dissolved in dry DMF (3.0 mL). KCO (0.14 g, 1.01 mmol) was added, and the rxn mixture was stirred at 120 °C for 5 h. LCMS showed product formation (m / z value, 345.2). The rxn mixture was diluted with water. The product was extracted with ethyl acetate. The combined ethyl acetate layers were washed with water and then brine. The organic layer was separated and dried over anhydrous sodium sulfate. The crude product was obtained by evaporating the solvent. The crude product was purified using an ISCO combi-flash chromatography system (mobile phase: EtOAc:hexane gradient). Yield: 0.14 g of product was isolated. 19 H 25 Calculated MS(ESI) mass for FNO is 344.43; [M+H] + The m / z value of was 345.2. Step 2: Synthesis of HBS-037-170: Compound HBS-037-167 (0.14 g, 0.4 mmol) was dissolved in MeOH (4.0 mL). 20.0% Pd-OH / C (28.0 mg) was added, and the rxn mixture was stirred at ambient temperature for 24 hours. LCMS showed unreacted starting material and product formation. 20.0% Pd-OH / C (20.0 mg) was further added, and the rxn mixture was stirred at ambient temperature for another 24 hours. LCMS showed product formation (m / z value, 225.1). The rxn mixture was filtered through Celite and washed with MeOH. The filtrate was evaporated under reduced pressure to give 67.0 mg of crude product (74.0% yield). This crude product was used in the next step without purification. C 11 H 17 The calculated MS(ESI) mass for FN4 is 224.28; [M+H] + The m / z value of was 225.1. [ka] Step 1: Synthesis of HBS-037-169: (S)-1-Boc-2-(aminomethyl)-pyrrolidine (0.2 g, 0.1 mmol) and 2-chloro-5-fluoro-pyrimidine (0.2 g, 1.5 mmol) were dissolved in anhydrous DMF (4.0 mL). K2CO3 (0.35 g, 2.5 mmol) was added, and the reaction mixture was heated at 100 °C for 5 hours. LCMS showed the formation of the product (m / z value, 297.0) and a by-product. The reaction mixture was cooled to ambient temperature and diluted with water. The product was extracted with ethyl acetate. The combined ethyl acetate layers were washed with water and then brine. The organic layer was separated and dried over anhydrous sodium sulfate. The crude product was obtained by evaporating the solvent. The crude product was purified using an ISCO combi-flash chromatography system (mobile phase: EtOAc:hexane gradient). 0.25 g of the major product was obtained (84.8% yield). C 14 H 21 Calculated MS(ESI) mass for FN4O2 is 296.34; [M+H] + The m / z value of was 297.0. Step 2: Synthesis of HBS-037-172: Compound HBS-037-169 (0.25 g, 0.85 mmol) was dissolved in anhydrous dioxane (3.0 mL). 4.0 M HCl in dioxane (2.1 mL, 8.47 mmol) was added, and the reaction was stirred at 50° C. for 5 hours. LCMS showed product formation (m / z value, 197.0). The reaction mixture was cooled to ambient temperature and concentrated under reduced pressure to give product 0.2 (68.0% yield). CH 13 The calculated MS(ESI) mass for FN4 is 196.22; [M+H] + The m / z value of was 197.0. [ka] Step 1: Synthesis of HBS-037-197: Tert-butyl-(2S)-2-(aminomethyl)piperidine-1-carboxylate (0.2 g, 0.93 mmol) and 2-chloro-5-trifluoromethylpyridine (0.2 g, 1.11 mmol) were dissolved in anhydrous DMF (5.0 mL). K2CO3 (0.32 g, 2.32 mmol) was added, and the reaction mixture was heated at 120 °C for 5 h. LCMS showed product formation (m / z value, 360.0). The reaction mixture was cooled to ambient temperature and diluted with water. The product was extracted with ethyl acetate. The combined ethyl acetate layers were washed with water and then brine. The organic layer was separated and dried over anhydrous sodium sulfate. The crude product was obtained by evaporating the solvent. The crude product was purified using an ISCO combi-flash chromatography system (mobile phase: EtOAc:hexane gradient). 0.17 g of product was obtained (50.6% yield). C 17 H 24 Calculated MS(ESI) mass for F3N3O2 is 359.39; [M+H] + The m / z value of was 360.0. Step 2: Synthesis of HBS-037-200: Compound HBS-037-197 (0.17 g, 0.47 mmol) was dissolved in anhydrous dioxane (5.0 mL). 4.0 M HCl in dioxane (1.2 mL, 4.7 mmol) was added, and the reaction was stirred at 50° C. for 5 hours. LCMS showed product formation (m / z value, 260.0). The reaction mixture was cooled to ambient temperature and concentrated under reduced pressure to give 0.17 g of product (yield). 12 H 16 Calculated MS(ESI) mass for F3N3 is 259.27; [M+H] + The m / z value of was 260.0.

[0055] General Experimental Methods for the Synthesis of Exemplary Compounds Method A: Acid intermediate 1.0 equiv (0.1 mmol) was dissolved in anhydrous DCM (2.0 mL). 1.5 equiv EDC·HCl (0.15 mmol) and 1.5 equiv HOBt (0.15 mmol) were added, followed by 5.0 equiv Et3N (0.5 mmol). The rxn mixture was stirred at ambient temperature for 5.0 min. The amine intermediate (0.1 mmol) was added to the rxn mixture. The rxn mixture was stirred at ambient temperature for 16 h. The rxn mixture was diluted with DCM and washed with saturated aqueous NaHCO3. The DCM layer was separated and dried over anhydrous Na2SO4. The crude product was obtained by evaporation of the solvent. The crude product was purified on an ISCO combi-flash system (mobile phase: ethyl acetate:hexane gradient or DCM:MeOH gradient).

[0056] Method B: 1.0 equivalents of the acid intermediate (0.1 mmol) and 1.1 equivalents of HATU (0.11 mmol) were dissolved in anhydrous DMF (1.5 mL). 4.0 equivalents of DIPEA (0.4 mmol) were added, and the rxn mixture was stirred at ambient temperature for 5 minutes. The amine intermediate (0.1 mmol) was added to the rxn mixture. The rxn mixture was stirred at ambient temperature for 16 hours. The rxn mixture was diluted with DCM and washed with saturated NaHCO3 solution. The DCM layer was separated and dried over anhydrous Na2SO4. The crude product was obtained by evaporation of the solvent. The crude product was purified on an ISCO combi-flash system (mobile phase: ethyl acetate:hexane gradient or DCM:MeOH gradient).

[0057] Table 2 outlines the acid intermediates, amine intermediates, and the methods used to prepare each example compound.

[0058] [Table 2] TIFF2025530768000139.tif253154TIFF2025530768000140.tif253157TIFF20255307680 00141.tif253156TIFF2025530768000142.tif253155TIFF2025530768000143.tif174158

[0059] II. Biological Assay Experiments The antagonistic activity of each example compound against both orexin receptors was measured by the following procedure. In vitro assay for measuring orexin antagonism: Intracellular calcium measurement: Chinese hamster ovary-derived (CHO) cells expressing human orexin receptors and human orexin-2 receptors, respectively, were grown in Ham's F-12 medium (L-glutamine supplemented with 300 μg / mL G418, 100 U / mL penicillin, 100 μg / mL streptomycin, and 10% heat-inactivated fetal calf serum (FCS)). The cells were seeded at 20,000 cells / well into a sterile, black-bottomed, clear, 384-well plate (Greiner). The plate was incubated overnight at 37°C, 5% CO2. The agonist, human orexin A, is prepared as a 1 mM stock solution (MeOH:water = 1:1) diluted in HBSS (containing 0.1% bovine serum albumin (BSA), NaHCO3 (0.375 g / L), and HEPES (20 mM)) to a final concentration of 3 nM for use in the assay.

[0060] Antagonists were prepared as 10 mM stock solutions (DMSO) and then diluted in DMSO into 384-well plates. The dilutions were then added to HBSS containing 0.1% bovine serum albumin (BSA), NaHCO3 (0.375 g / L), and HEPES (20 mM). On the day of the assay, 50 μL of staining buffer (HBSS containing 1% FCS, HEPES (20 mM), NaHCO3 (0.375 g / L), 5 mM probenecid (Sigma), and 3 μM fluorescent calcium indicator fluo-4 AM (1 mM stock solution in DMSO with 10% Pluronic)) was added to each well. The 384-well cell plate was incubated at 37°C and 5% CO2 for 50 minutes, then equilibrated to room temperature for 30 minutes before measurement.

[0061] Antagonists are added to the plate in a volume of 10 μL / well in a fluorescence imaging plate reader (FLIPR Tetra, Molecular Devices) and incubated for 120 minutes, followed by the final addition of agonists at 10 μL / well. Fluorescence in each well is measured at 1-second intervals, and the height of each fluorescence peak is compared to that elicited by 3 nM orexin-A containing vehicle instead of antagonist. IC50 values ​​(compound concentration required to inhibit 50% of the agonistic response) are measured and may be normalized using the IC50 value obtained for the on-plate reference compound. Optimal conditions were achieved by adjusting the pipetting speed and cell splitting regime. Calculated IC 50 The values ​​will vary from day to day and from cell assay to cell assay. This type of variation is known to those skilled in the art. 50 If values ​​are measured multiple times, IC 50 The geometric mean of the values ​​is obtained. The antagonist activity of exemplary compounds is shown in Table 3.

[0062] Human kappa-opioid (KOP) receptor (agonist radioligand) binding assay the purpose Evaluation of the affinity of compounds for human κ-opioid receptors in transformed RBL cells (assessed by radioligand binding assay).

[0063] Experimental protocol Cell membrane homogenates (approximately 80 μg of protein) were incubated with 0.5 nM [H]U-69593 in a buffer containing 50 mM Tris-HCl (pH 7.4), 10 mM MgCl2, and 1 mM EDTA for 60 minutes at 22°C in the absence or presence of test compounds. Nonspecific binding was measured in the presence of 10 μM naloxone. After incubation, samples were rapidly filtered under vacuum through glass fiber filters (GF / B, Packard) presoaked with 0.3% PEI and rinsed several times with ice-cold 50 mM Tris-HCl using a 96-sample cell harvester (Unifilter, Packard). After drying, the filters were counted using a scintillation counter (Topcount, Packard) with scintillation cocktail (Microscint 0, Packard). Results are expressed as % inhibition of control radioligand-specific binding. The standard reference compound is U-50488, which is tested at multiple concentrations in each experiment to generate a competition curve for the purpose of calculating its IC50.

[0064] [Table 3] JPEG2025530768000145.jpg232158TIFF2025530768000146.tif233158TIFF2025530768000147.tif125158TIFF20255307680 00148.tif236158TIFF2025530768000149.tif216158TIFF2025530768000150.tif209158JPEG2025530768000151.jpg242158 JPEG2025530768000152.jpg250158JPEG2025530768000153.jpg215158JPEG2025530768000154.jpg234158JPEG20255307680 00155.jpg237158JPEG2025530768000156.jpg219158J...

Claims

1. Chemical formula (I) or (II): 【Chemical 1】 or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof; where R １ contains an E that is a carbon (C) but not a nitrogen (N), and in formula I, E is linked to J or D by a double bond, or in formula II, E is linked to A or D by a double bond; and R １ is selected from the group consisting of H, alkyl, alkoxy, cycloalkyl, phenyl, aromatic or aryl, heteroaryl which is optionally a 5- or 6-membered heteroaryl, substituted aromatic or aryl, and substituted heteroaryl which is optionally a 5- or 6-membered heteroaryl; Here, R １ is heteroaryl, then R １ is optionally a 5- or 6-membered heteroaryl selected from the group consisting of pyrazolyl, triazolyl, oxazolyl, thiazolyl, thiophenyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl; wherein said aromatic, aryl or heteroaryl is unsubstituted, mono- or di-substituted; wherein the substituents are independently: (C １～４ ) alkyl, (C １～４ ) alkoxy, halogen, (C １～３ ) fluoroalkyl, (C １～３ ) fluoroalkoxy and (C ３～７ ) cycloalkyl; R ２ , R ３ , and R ４ are independently H, alkyl, substituted alkyl, (C １～４ ) alkyl, (C １～４ ) alkoxy, (C １～３ ) fluoroalkyl, (C １～３ ) fluoroalkoxy, (C ３～７ ) cycloalkyl, and halogen (optionally F, Cl, or Br); Here, R ２ , R ３ and R ４ each independently and optionally at each substitutable position, R ２ , R ３ and R ４ substituted by one, two, or all up to three independently selected substituents of R ５ But H, F, CH ３ , alkyl, substituted alkyl, (C １～３ ) Fluoroalkyl, cycloalkyl, and Y, Z １ and Z ２ R substituted at a carbon having ５ is selected from the group consisting of Here, R ５ ' is defined herein; R ５ ' is selected from the group consisting of aromatic, aryl, heteroaryl, 5- or 6-membered heteroaryl, substituted aromatic or aryl, substituted heteroaryl or fused two heteroaryl ring systems, optionally containing a 5- or 6-membered ring; wherein said aromatic, aryl or heteroaryl is unsubstituted, mono- or di- or tri-substituted; wherein the substituents are independently: (C １～４ ) alkyl, (C １～４ ) alkoxy, halogen, (C １～３ ) fluoroalkyl, (C １～３ ) fluoroalkoxy, (C ３～７ ) cycloalkyl, and (C ３～７ ) heterocycloalkyl; R ６ But H, F, CH ３ , alkyl, substituted alkyl, (C １～３ ) fluoroalkyl, cycloalkyl, R ６ (C １～３ ) R as alkyl forming the cyclic structure of the alkyl bridge １０ or R １１ connected to one of the following: R ７ But H, F, CH ３ , alkyl, substituted alkyl, (C １～３ ) fluoroalkyl, cycloalkyl, R ７ is Y, Z １ and Z ２ where R ５ ' is defined herein; R ８ But H, F, CH ３ , alkyl, substituted alkyl, (C １～３ ) fluoroalkyl, cycloalkyl, R ８ is (C １～３ ) R as alkyl forming the cyclic structure of the alkyl bridge １０ , R １１ or R １２ is connected to either R ９ But H, F, CH ３ , alkyl, substituted alkyl, (C １～３ ) fluoroalkyl, cycloalkyl, R ９ is (C １～３ ) R as alkyl forming the cyclic structure of the alkyl bridge ６ or R １２ is connected to; R １０ But H, F, CH ３ , alkyl, substituted alkyl, (C １～３ ) fluoroalkyl, cycloalkyl, R １０ is (C １～３ ) R as alkyl forming the cyclic structure of the alkyl bridge ６ or R １１ is connected to; R １１ But H, F, CH ３ , alkyl, substituted alkyl, (C １～３ ) fluoroalkyl, cycloalkyl, R １１ is (C １～３ ) R as alkyl forming the cyclic structure of the alkyl bridge ６ is connected to; R １２ But H, F, CH ３ , alkyl, substituted alkyl, (C １～３ ) fluoroalkyl, cycloalkyl, R １２ is (C １～３ ) R as alkyl forming the cyclic structure of the alkyl bridge ９ is connected to; X is optionally absent to provide a 5-membered pyrrolidine ring; CH ２ , O, and C.R. ａ R ｂ where R ａ and R ｂ is selected from the group consisting of alkyl, cycloalkyl, and fluoroalkyl; and here: the carbon atom at position 2 of said piperidine or pyrrolidine is optionally in the absolute (S) configuration; or the carbon atom at position 2 of the morpholine ring (where X is oxygen) is optionally in the absolute (R) configuration; Y is Z １ Groups and Z ２ R directly connected to the carbon bearing the group ５ '; O; NH; CH ２ OR ５ ';CH ２ ;NR ａ is selected from the group consisting of Here, R ａ is selected from the group consisting of alkyl, cycloalkyl, and heteroalkyl, and the 5- or 6-membered heteroaryl is selected from the group consisting of pyrrolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, and oxadiazolyl; and Z １ and Z ２ are independently H, F, (C １～４ ) alkyl, (C １～３ ) fluoroalkyl, (C １～３ ) fluoroalkoxy, and (C ２～７ ) cycloalkyl; and here: The fused or unfused ring system A-B-J-D-E is a 5-membered heteroaryl, optionally imidazole (where A and J are nitrogen, while B, E, D are carbon); pyrazole (where A and B are nitrogen, while D, E, and J are carbon); optionally fused to one or more further ring systems or unfused; the fused ring system B-J-M-G-K-L is an arrangement of the variables as outlined above, providing the group consisting of 6-membered aromatic, 6-membered aryl, 6-membered substituted aromatic, 6-membered substituted aryl, 6-membered substituted heteroaryl, 6-membered unsubstituted heteroaryl, 5- or 6-membered cycloalkyl, and 5- or 6-membered heterocycloalkyl; and where optionally: A is nitrogen, optionally imidazole or pyrazole; B is carbon or nitrogen; J is carbon or nitrogen; D is carbon; E is carbon, where R １ is a group as defined above; M is carbon, CH, CHR ２ , CHR ３ , C.R. ２ R ３ , C.R. ２ , C.R. ３ , C.R. ４ , O, and N; G is carbon, CH, CHR ２ , CHR ３ , C.R. ２ R ３ , C.R. ２ , C.R. ３ , C.R. ４ and O; K is carbon, CH, CHR ２ , CHR ３ , C.R. ２ R ３ , C.R. ２ , C.R. ３ , C.R. ４ and O; and L is carbon, CH, CHR ２ , CHR ３ , C.R. ２ R ３ , C.R. ２ , C.R. ３ , C.R. ４ , O, and N; The compound, or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof.

2. Chemical formula I-a or II-a: 【Chemistry 2】 10. The compound of claim 1 having the formula: where R １ is selected from the group consisting of H, alkyl, alkoxy, cycloalkyl, phenyl, aromatic or aryl, heteroaryl which is optionally a 5- or 6-membered heteroaryl, substituted aromatic or aryl, and substituted heteroaryl which is optionally a 5- or 6-membered heteroaryl; Here, R １ When is heteroaryl, R １ is optionally a 5- or 6-membered heteroaryl selected from the group consisting of pyrazolyl, triazolyl, oxazolyl, thiazolyl, thiophenyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl; wherein said aromatic, aryl or heteroaryl is unsubstituted, mono- or di-substituted; wherein the substituents are independently: (C １～４ ) alkyl, (C １～４ ) alkoxy, halogen, (C １～３ ) fluoroalkyl, (C １～３ ) fluoroalkoxy and (C ３～７ ) cycloalkyl; R ２ , R ３ , and R ４ are independently H, alkyl, substituted alkyl, (C １～４ ) alkyl, (C １～４ ) alkoxy, (C １～３ ) fluoroalkyl, (C １～３ ) fluoroalkoxy, (C ３～７ ) selected from the group consisting of cycloalkyl, halogen (optionally F, Cl, or Br); Here, R ２ , R ３ and R ４ each independently and optionally at each substitutable position, R ２ , R ３ and R ４ substituted by one, two, or all up to three independently selected substituents of R ５ But H, F, CH ３ , alkyl, substituted alkyl, (C １～３ ) Fluoroalkyl, cycloalkyl, and Y, Z １ and Z ２ R substituted with a carbon having ５ is selected from the group consisting of Here, R ５ ' is defined herein; R ５ ' is selected from the group consisting of aromatic, aryl, heteroaryl, 5- or 6-membered heteroaryl, substituted aromatic or aryl, substituted heteroaryl or fused two heteroaryl ring systems, optionally containing a 5- or 6-membered ring; wherein said aromatic, aryl or heteroaryl is unsubstituted, mono- or di- or tri-substituted; wherein the substituents are independently: (C １～４ ) alkyl, (C １～４ ) alkoxy, halogen, (C １～３ ) fluoroalkyl, (C １～３ ) fluoroalkoxy, (C ３～７ ) cycloalkyl, and (C ３～７ ) heterocycloalkyl; R ６ But H, F, CH ３ , alkyl, substituted alkyl, (C １～３ ) fluoroalkyl, cycloalkyl, R ６ (C １～３ ) R as alkyl forming the cyclic structure of the alkyl bridge １０ or R １１ connected to one of the following: R ７ But H, F, CH ３ , alkyl, substituted alkyl, (C １～３ ) fluoroalkyl, cycloalkyl, R ７ is Y, Z １ and Z ２ where R ５ ' is defined herein; R ８ But H, F, CH ３ , alkyl, substituted alkyl, (C １～３ ) fluoroalkyl, cycloalkyl, R ８ is (C １～３ ) R as alkyl forming the cyclic structure of the alkyl bridge １１ or R １２ is connected to; R ９ But H, F, CH ３ , alkyl, substituted alkyl, (C １～３ ) fluoroalkyl, cycloalkyl, R ９ is (C １～３ ) R as alkyl forming the cyclic structure of the alkyl bridge ６ or R １２ is connected to; R １０ But H, F, CH ３ , alkyl, substituted alkyl, (C １～３ ) fluoroalkyl, cycloalkyl, R １０ is (C １～３ ) R as alkyl forming the cyclic structure of the alkyl bridge ６ or R １１ is connected to; R １１ But H, F, CH ３ , alkyl, substituted alkyl, (C １～３ ) fluoroalkyl, cycloalkyl, R １１ is (C １～３ ) R as alkyl forming the cyclic structure of the alkyl bridge ６ is connected to; R １２ But H, F, CH ３ , alkyl, substituted alkyl, (C １～３ ) fluoroalkyl, cycloalkyl, R １２ is (C １～３ ) R as alkyl forming the cyclic structure of the alkyl bridge ９ is connected to; X is optionally absent to provide a 5-membered pyrrolidine ring; CH ２ , O, and C.R. ａ R ｂ where R ａ and R ｂ is selected from the group consisting of alkyl, cycloalkyl, and fluoroalkyl; and here: the carbon atom at position 2 of the piperidine or pyrrolidine ring is optionally in the absolute (S) configuration; or the carbon atom at position 2 of the morpholine ring (where X is oxygen) is optionally in the absolute (R) configuration; Y is Z １ Groups and Z ２ R directly connected to the carbon bearing the group ５ '; O; NH; CH ２ OR ５ ';CH ２ ;NR ａ is selected from the group consisting of Here, R ａ is selected from the group consisting of alkyl, cycloalkyl, and heteroalkyl, and the 5- or 6-membered heteroaryl is selected from the group consisting of pyrrolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, and oxadiazolyl; Z １ and Z ２ are independently H, F, (C １～４ ) alkyl, (C １～３ ) fluoroalkyl, (C １～３ ) fluoroalkoxy, and (C ２～７ ) cycloalkyl; Where: wherein the fused ring system B-J-M-G-K-L is selected from the arrangements of the variables outlined above to provide the group consisting of 6-membered aromatic, 6-membered aryl, 6-membered substituted aromatic, 6-membered substituted aryl, 6-membered substituted heteroaryl, 6-membered unsubstituted heteroaryl, 5- or 6-membered cycloalkyl, and 5- or 6-membered heterocycloalkyl; and preferably: M is carbon, CH, CHR ２ , CHR ３ , C.R. ２ R ３ , C.R. ２ , C.R. ３ , C.R. ４ , O, and N; G is carbon, CH, CHR ２ , CHR ３ , C.R. ２ R ３ , C.R. ２ , C.R. ３ , C.R. ４ and O; K is carbon, CH, CHR ２ , CHR ３ , C.R. ２ R ３ , C.R. ２ , C.R. ３ , C.R. ４ and O, or is absent to provide 5-membered cycloalkyl, and heterocycloalkyl; and L is carbon, CH, CHR ２ , CHR ３ , C.R. ２ R ３ , C.R. ２ , C.R. ３ , C.R. ４ , O, and N; The compound, or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof.

3. Chemical formula I-b or II-b: 【Chemistry 3】 10. The compound of claim 1, or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof, having the formula: where R １ is selected from the group consisting of H, alkyl, alkoxy, cycloalkyl, phenyl, aromatic or aryl, heteroaryl which is optionally a 5- or 6-membered heteroaryl, substituted aromatic or aryl, and substituted heteroaryl which is optionally a 5- or 6-membered heteroaryl; Here, R １ When is heteroaryl, R １ is optionally a 5- or 6-membered heteroaryl selected from the group consisting of pyrazolyl, triazolyl, oxazolyl, thiazolyl, thiophenyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl; wherein said aromatic, aryl or heteroaryl is unsubstituted, mono- or di-substituted; wherein the substituents are independently: (C １～４ ) alkyl, (C １～４ ) alkoxy, halogen, (C １～３ ) fluoroalkyl, (C １～３ ) fluoroalkoxy and (C ３～７ ) cycloalkyl; R ２ , R ３ , and R ４ are independently H, halogen (F, Cl, Br, etc.), alkyl, substituted alkyl, (C １～４ ) alkyl, (C １～４ ) alkoxy, (C １～３ ) fluoroalkyl, (C １～３ ) fluoroalkoxy and (C ３～７ ) cycloalkyl; Here, R ２ , R ３ and R ４ each independently and optionally at each substitutable position, R ２ , R ３ and R ４ substituted by one, two, or all up to three independently selected substituents of R ５ But H, F, CH ３ , alkyl, substituted alkyl, (C １～３ ) Fluoroalkyl, cycloalkyl, and Y, Z １ and Z ２ R substituted with a carbon having ５ is selected from the group consisting of Here, R ５ ' is defined herein; R ５ ' is selected from the group consisting of aromatic, aryl, heteroaryl, 5- or 6-membered heteroaryl, substituted aromatic or aryl, substituted heteroaryl or fused two heteroaryl ring systems, optionally containing a 5- or 6-membered ring; wherein said aromatic, aryl or heteroaryl is unsubstituted, mono- or di- or tri-substituted; wherein the substituents are independently: (C １～４ ) alkyl, (C １～４ ) alkoxy, halogen, (C １～３ ) fluoroalkyl, (C １～３ ) fluoroalkoxy, (C ３～７ ) cycloalkyl, and (C ３～７ ) heterocycloalkyl; R ６ But H, F, CH ３ , alkyl, substituted alkyl, (C １～３ ) fluoroalkyl, cycloalkyl, R ６ (C １～３ ) R as alkyl forming the cyclic structure of the alkyl bridge １０ or R １１ connected to one of the following: R ７ But H, F, CH ３ , alkyl, substituted alkyl, (C １～３ ) fluoroalkyl, cycloalkyl, R ７ is Y, Z １ and Z ２ where R ５ ' is defined herein; R ８ But H, F, CH ３ , alkyl, substituted alkyl, (C １～３ ) fluoroalkyl, cycloalkyl, R ８ is (C １～３ ) R as alkyl forming the cyclic structure of the alkyl bridge １０ , R １１ or R １２ is connected to either R ９ But H, F, CH ３ , alkyl, substituted alkyl, (C １～３ ) fluoroalkyl, cycloalkyl, R ９ is (C １～３ ) R as alkyl forming the cyclic structure of the alkyl bridge ６ or R １２ is connected to; R １０ But H, F, CH ３ , alkyl, substituted alkyl, (C １～３ ) fluoroalkyl, cycloalkyl, R １０ is (C １～３ ) R as alkyl forming the cyclic structure of the alkyl bridge ６ or R １１ is connected to; R １１ But H, F, CH ３ , alkyl, substituted alkyl, (C １～３ ) fluoroalkyl, cycloalkyl, R １１ is (C １～３ ) R as alkyl forming the cyclic structure of the alkyl bridge ６ is connected to; R １２ But H, F, CH ３ , alkyl, substituted alkyl, (C １～３ ) fluoroalkyl, cycloalkyl, R １２ is (C １～３ ) R as alkyl forming the cyclic structure of the alkyl bridge ９ is connected to; X is optionally absent to provide a 5-membered pyrrolidine ring; CH ２ , O, and C.R. ａ R ｂ where R ａ and R ｂ is selected from the group consisting of alkyl, cycloalkyl, and fluoroalkyl; and here: the carbon atom at position 2 of said piperidine or pyrrolidine is optionally in the absolute (S) configuration; or the carbon atom at position 2 of the morpholine ring (where X is oxygen) is optionally in the absolute (R) configuration; Y is Z １ Groups and Z ２ Absent in order to provide R5' directly linked to the carbon bearing the group; O; NH; CH ２ OR ５ ';CH ２ ;NR ａ is selected from the group consisting of Here, R ａ is selected from the group consisting of alkyl, cycloalkyl, and heteroalkyl, and the 5- or 6-membered heteroaryl is selected from the group consisting of pyrrolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, and oxadiazolyl; Z １ and Z ２ are independently H, F, (C １～４ ) alkyl, (C １～３ ) fluoroalkyl, (C １～３ ) fluoroalkoxy, and (C ２～７ ) cycloalkyl; Where: wherein the fused ring system B-J-M-G-K-L is selected from the arrangements of the variables outlined above to provide the group consisting of 6-membered aromatic, 6-membered aryl, 6-membered substituted aromatic, 6-membered substituted aryl, 6-membered substituted heteroaryl, 6-membered unsubstituted heteroaryl, 5- or 6-membered cycloalkyl, and 5- or 6-membered heterocycloalkyl; and preferably: M is carbon, CH, CHR ２ , CHR ３ , C.R. ２ R ３ , C.R. ２ , C.R. ３ , C.R. ４ , O, and N; G is carbon, CH, CHR ２ , CHR ３ , C.R. ２ R ３ , C.R. ２ , C.R. ３ , C.R. ４ and O; K is carbon, CH, CHR ２ , CHR ３ , C.R. ２ R ３ , C.R. ２ , C.R. ３ , C.R. ４ and O, or is absent to provide 5-membered cycloalkyl, and heterocycloalkyl; and L is carbon, CH, CHR ２ , CHR ３ , C.R. ２ R ３ , C.R. ２ , C.R. ３ , C.R. ４ , O, and N; The compound, or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof.

4. Compounds of formula I-a4, I-a5, I-a6, II-a4, II-a5, or II-a6: 【Chemistry 4】 10. The compound of claim 1, or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof, having the formula: Where: R １ is selected from the group consisting of H, alkyl, alkoxy, cycloalkyl, phenyl, aromatic or aryl, heteroaryl which is optionally a 5- or 6-membered heteroaryl, substituted aromatic or aryl, and substituted heteroaryl which is optionally a 5- or 6-membered heteroaryl; Here, R １ When is heteroaryl, R １ is optionally a 5- or 6-membered heteroaryl selected from the group consisting of pyrazolyl, triazolyl, oxazolyl, thiazolyl, thiophenyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl; wherein said aromatic, aryl or heteroaryl is unsubstituted, mono- or di-substituted; wherein the substituents are independently: (C １～４ ) alkyl, (C １～４ ) alkoxy, halogen, (C １～３ ) fluoroalkyl, (C １～３ ) fluoroalkoxy and (C ３～７ ) cycloalkyl; R ２ , R ３ , and R ４ are independently H, halogen (F, Cl, Br, etc.), alkyl, substituted alkyl, (C １～４ ) alkyl, (C １～４ ) alkoxy, (C １～３ ) fluoroalkyl, (C １～３ ) fluoroalkoxy and (C ３～７ ) cycloalkyl; Here, R ２ , R ３ and R ４ each independently and optionally at each substitutable position, R ２ , R ３ and R ４ substituted by one, two, or all up to three independently selected substituents of R ５ is H, or Y, Z １ and Z ２ where R ５ ' is defined herein; R ５ ' is selected from the group consisting of aromatic, aryl, heteroaryl, 5- or 6-membered heteroaryl, substituted aromatic or aryl, substituted heteroaryl or fused two heteroaryl ring systems, optionally containing a 5- or 6-membered ring; wherein said aromatic, aryl or heteroaryl is unsubstituted, mono- or di- or tri-substituted; wherein the substituents are independently: (C １～４ ) alkyl, (C １～４ ) alkoxy, halogen, (C １～３ ) fluoroalkyl, (C １～３ ) fluoroalkoxy, (C ３～７ ) cycloalkyl, and (C ３～７ ) heterocycloalkyl; R ６ But H, F, CH ３ , alkyl, substituted alkyl, (C １～３ ) fluoroalkyl, cycloalkyl, R ６ (C １～３ ) R as alkyl forming the cyclic structure of the alkyl bridge １０ or R １１ connected to one of the following: R ７ is H, or Y, Z １ and Z ２ where R ５ ' is defined herein; R ８ But H, F, CH ３ , alkyl, substituted alkyl, (C １～３ ) fluoroalkyl, cycloalkyl, R ８ is (C １～３ ) R as alkyl forming the cyclic structure of the alkyl bridge １０ , R １１ or R １２ is connected to either R ９ But H, F, CH ３ , alkyl, substituted alkyl, (C １～３ ) fluoroalkyl, cycloalkyl, R ９ is (C １～３ ) R as alkyl forming the cyclic structure of the alkyl bridge ６ or R １２ is connected to; R １０ But H, F, CH ３ , alkyl, substituted alkyl, (C １～３ ) fluoroalkyl, cycloalkyl, R １０ is (C １～３ ) R as alkyl forming the cyclic structure of the alkyl bridge ６ or R １１ is connected to; R １２ But H, F, CH ３ , alkyl, substituted alkyl, (C １～３ ) fluoroalkyl, cycloalkyl, R １２ is (C １～３ ) R as alkyl forming the cyclic structure of the alkyl bridge ９ is connected to; X is optionally absent to provide a 5-membered pyrrolidine ring; CH ２ , O, and C.R. ａ R ｂ where R ａ and R ｂ is selected from the group consisting of alkyl, cycloalkyl, and fluoroalkyl; and here: the carbon atom at position 2 of said piperidine or pyrrolidine is optionally in the absolute (S) configuration; or the carbon atom at position 2 of the morpholine ring (where X is oxygen) is optionally in the absolute (R) configuration; Y is Z １ Groups and Z ２ R directly connected to the carbon bearing the group ５ '; O; NH; CH ２ OR ５ ';CH ２ ;NR ａ is selected from the group consisting of Here, R ａ is selected from the group consisting of alkyl, cycloalkyl, and heteroalkyl, and the 5- or 6-membered heteroaryl is selected from the group consisting of pyrrolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, and oxadiazolyl; and Z １ and Z ２ are independently H, F, (C １～４ ) alkyl, (C １～３ ) fluoroalkyl, (C １～３ ) fluoroalkoxy, and (C ２～７ ) cycloalkyl; and preferably: L is carbon, CH, CHR ２ , CHR ３ , C.R. ２ R ３ , C.R. ２ , C.R. ３ , C.R. ４ and N, The compound, or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof.

5. Compounds of formula I-b4, I-b5, I-b6, II-b4, II-b5, or II-b6: 【Chemistry 5】 10. The compound of claim 1, or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof, having the formula: where R １ is selected from the group consisting of H, alkyl, alkoxy, cycloalkyl, phenyl, aromatic or aryl, heteroaryl which is optionally a 5- or 6-membered heteroaryl, substituted aromatic or aryl, and substituted heteroaryl which is optionally a 5- or 6-membered heteroaryl; Here, R １ When is heteroaryl, R １ is optionally a 5- or 6-membered heteroaryl selected from the group consisting of pyrazolyl, triazolyl, oxazolyl, thiazolyl, thiophenyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl; wherein said aromatic, aryl or heteroaryl is unsubstituted, mono- or di-substituted; wherein the substituents are independently: (C １～４ ) alkyl, (C １～４ ) alkoxy, halogen, (C １～３ ) fluoroalkyl, (C １～３ ) fluoroalkoxy and (C ３～７ ) cycloalkyl; R ２ , R ３ , and R ４ are independently H, halogen (F, Cl, Br, etc.), alkyl, substituted alkyl, (C １～４ ) alkyl, (C １～４ ) alkoxy, (C １～３ ) fluoroalkyl, (C １～３ ) fluoroalkoxy and (C ３～７ ) cycloalkyl; Here, R ２ , R ３ and R ４ each independently and optionally at each substitutable position, R ２ , R ３ and R ４ substituted by one, two, or all up to three independently selected substituents of R ５ is H, or Y, Z １ and Z ２ where R ５ ' is defined herein; R ５ ' is selected from the group consisting of aromatic, aryl, heteroaryl, 5- or 6-membered heteroaryl, substituted aromatic or aryl, substituted heteroaryl or fused two heteroaryl ring systems, optionally containing a 5- or 6-membered ring; wherein said aromatic, aryl or heteroaryl is unsubstituted, mono- or di- or tri-substituted; wherein the substituents are independently: (C １～４ ) alkyl, (C １～４ ) alkoxy, halogen, (C １～３ ) fluoroalkyl, (C １～３ ) fluoroalkoxy, (C ３～７ ) cycloalkyl, and (C ３～７ ) heterocycloalkyl; R ６ But H, F, CH ３ , alkyl, substituted alkyl, (C １～３ ) fluoroalkyl, cycloalkyl, R ６ (C １～３ ) R as alkyl forming the cyclic structure of the alkyl bridge １０ or R １１ connected to one of the following: R ７ is H, or Y, Z １ and Z ２ where R ５ ' is defined herein; R ８ But H, F, CH ３ , alkyl, substituted alkyl, (C １～３ ) fluoroalkyl, cycloalkyl, R ８ is (C １～３ ) R as alkyl forming the cyclic structure of the alkyl bridge １０ , R １１ or R １２ is connected to either R ９ But H, F, CH ３ , alkyl, substituted alkyl, (C １～３ ) fluoroalkyl, cycloalkyl, R ９ is (C １～３ ) R as alkyl forming the cyclic structure of the alkyl bridge ６ or R １２ is connected to; R １０ But H, F, CH ３ , alkyl, substituted alkyl, (C １～３ ) fluoroalkyl, cycloalkyl, R １０ is (C １～３ ) R as alkyl forming the cyclic structure of the alkyl bridge ６ or R １１ is connected to; R １２ But H, F, CH ３ , alkyl, substituted alkyl, (C １～３ ) fluoroalkyl, cycloalkyl, R １２ is (C １～３ ) R as alkyl forming the cyclic structure of the alkyl bridge ９ is connected to; X is optionally absent to provide a 5-membered pyrrolidine ring; CH ２ , O, and C.R. ａ R ｂ where R ａ and R ｂ is selected from the group consisting of alkyl, cycloalkyl, and fluoroalkyl; and here: the carbon atom at position 2 of the piperidine or pyrrolidine ring is optionally in the absolute (S) configuration; or the carbon atom at position 2 of the morpholine ring (where X is oxygen) is optionally in the absolute (R) configuration; Y is Z １ Groups and Z ２ Absent in order to provide R5' directly linked to the carbon bearing the group; O; NH; CH ２ OR ５ ';CH ２ ;NR ａ is selected from the group consisting of Here, R ａ is selected from the group consisting of alkyl, cycloalkyl, and heteroalkyl, and the 5- or 6-membered heteroaryl is selected from the group consisting of pyrrolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, and oxadiazolyl; and Z １ and Z ２ are independently H, F, (C １～４ ) alkyl, (C １～３ ) fluoroalkyl, (C １～３ ) fluoroalkoxy, and (C ２～７ ) cycloalkyl; and preferably: M is carbon, CH, CHR ２ , CHR ３ , C.R. ２ R ３ , C.R. ２ , C.R. ３ , C.R. ４ , or N; The compound, or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof.

6. Examples 1-263: 【Chemistry 6】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof.

7. 10. The compound of claim 6, or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof, selected from the group consisting of the compounds of Examples 4, 6, 7, 8, 10, 12, 13, 20, 22, 24, 25-29, 34, 40, 42-50, 53-64, 66-69, 73, 75, 78, 80, 89, 90, 92, 94, 95, 97, 107, 111, 112, 117-119, 122-142, 147-151, 156, 158, 171-183, 185-198, 201-203, 205, 207, 208, 210-214, 223, and 224.

8. 8. The compound of claim 6 or 7, or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof, selected from the group consisting of compounds of Examples 53, 55, 66, 95, 112, 118, 119, 122, 123, 124, 129, 130, 131, 134, 135, 138, 139, 140, 141, 142, 147, 148, 156, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 191, 195, 203, 205, 211, 223, and 224.

9. A compound of any preceding claim, which is unlabeled or isotopically labeled.

10. A compound according to any preceding claim, or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof; and at least one pharmaceutically acceptable carrier, adjuvant and / or vehicle; A pharmaceutical composition comprising:

11. 10. The pharmaceutical composition of claim 8, comprising a therapeutically effective amount of the compound, its pharmaceutically acceptable salts, hydrates, solvates, polymorphs, isomers, and / or combinations thereof.

12. 12. The pharmaceutical composition according to claim 10 or 11, wherein the composition further comprises at least one second therapeutic agent.

13. 10. A method of antagonizing and / or modulating at least one orexin receptor and / or at least one kappa-opioid receptor in a cell, comprising exposing the cell to a compound and / or composition according to any preceding claim, wherein optionally the method is an in vitro method.

14. 10. A method of modulating at least one orexin receptor and / or at least one kappa-opioid receptor in a subject in need thereof, comprising administering a compound and / or composition according to any preceding claim.

15. A method of treating a condition selected from the group consisting of substance addiction, substance dependence, panic, anxiety, depression, post-traumatic stress disorder (PTSD), neurodegeneration, autism, schizophrenia, pain, Alzheimer's disease (AD), and central nervous system (CNS) disorders in a subject in need thereof, comprising administering a compound and / or composition according to any preceding claim.

16. 16. The method of claim 15, wherein the substance to which the substance addiction or substance dependence is addressed is one or more opioids (optionally, heroin, morphine, oxycodone, fentanyl, and hydrocodone); one or more stimulants optionally selected from the group consisting of amphetamine, cocaine, crack cocaine, and methamphetamine; and one or more sedatives and / or tranquilizers, benzodiazepines, and barbiturates; The method is selected from the group consisting of:

17. 17. The method of any one of claims 13 to 16, wherein the compound antagonizes at least one orexin receptor and / or antagonizes or modulates at least one kappa-opioid receptor.

18. A method of making a compound or composition of any preceding claim using at least one available combination of acid intermediates, amine intermediates, and methods set out in Table 2.

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